Gary Siuzdak | |
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Born | December 29, 1961 |
Scientific career | |
Fields | Analytical Chemistry, Metabolomics |
Gary Siuzdak is an American chemist best known for his work in the field of metabolomics, [1] [2] activity metabolomics [3] [4] [5] [6] [7] (a termed coined in 2019 [8] ), and mass spectrometry. [9] [10] [11] [12] [13] [14] His lab discovered indole-3-propionic acid as a gut bacteria derived metabolite in 2009. [15] [16] [17] He is currently the Professor and Director of The Center for Metabolomics and Mass Spectrometry at Scripps Research in La Jolla, California. [18] Siuzdak has also made contributions to virus analysis, [19] [20] viral structural dynamics, [21] [22] [23] as well as developing mass spectrometry imaging technology using nanostructured surfaces. [11] [24] The Siuzdak lab is also responsible for creating the research tools eXtensible Computational Mass Spectrometry (XCMS), [9] [25] METLIN, [13] METLIN Neutral Loss [26] and Q-MRM. [27] [28] [29] As of January 2021, [30] the XCMS/METLIN platform has over 50,000 registered users.
Siuzdak studied chemistry (B.S.) and applied mathematics (B.A.) at Rhode Island College. He then went to Dartmouth College for his graduate work where he built his first mass spectrometer [31] to perform multi-photon ionization mass spectrometry experiments and occasionally competed in powerlifting. [32] At Dartmouth he received his Ph.D. in Physical Chemistry (March 29, 1990) and on April 1, 1990, started at Scripps Research. [18] In 2017 Siuzdak received an honorary doctorate (with Emmanuelle Charpentier) from Umeå University [33] for his work in metabolomics. Siuzdak has hundreds of papers and has authored two books: Mass Spectrometry for Biotechnology (1996) and The Expanding Role of Mass Spectrometry in Biotechnology (2003) as well as The Expanding Role of Mass Spectrometry in Biotechnology 2nd Ed. (2006). [34]
From 1994 to the present the Siuzdak lab has been working on activity metabolomics. [1] [3] [4] [5] [9] [12] [35] [15] [36] [37] using liquid chromatography mass spectrometry-based metabolomics to identify metabolites that alter phenotype. [1] [3] [4] [5] [35] [15] [36] [37] [12] His initial efforts with Richard Lerner, [4] used liquid chromatography mass spectrometry to perform metabolomic experiments on the cerebral spinal fluid of sleep deprived animals. cis-9,10-octadecenoamide , a novel lipid hormone (also known as oleamide), [4] was observed and shown to have sleep inducing properties. This work is one of the earliest such experiments combining liquid chromatography mass spectrometry and metabolomics to identify active metabolites. [4] [1] [3] Another notable activity metabolomics effort with Oscar Yanes (Spain) identified [5] neuroprotectin D1 as a metabolite that promotes stem cell differentiation.
In 1996 whole virus analysis was performed with an electrospray ionization mass spectrometer where the virus was collected and successfully tested for viability. [19] Later, he and his collaborators provided the first example of a whole intact virus (tobacco mosaic virus) being mass measured using a charge detection mass spectrometer, an instrument designed by Henry Benner and Stephen Fuerstenau at Lawrence Berkeley National Labs. [20]
In 1999, the Siuzdak lab described the use of nanostructures to enhance desorption/ionization on porous silicon of small molecules (DIOS), [10] this is also known as the first surface-based example of surface-assisted laser desorption/ionization mass spectrometry (SALDI-MS). This technology went on to be expanded using fluorinated initiator molecules used within the porous silicon and was described as Nanostructure Initiator Mass Spectrometry (NIMS), [11] it is also known as Nanostructure Imaging Mass Spectrometry (NIMS) because of its expanded application to imaging. [11] [24]
In 2005, the Siuzdak lab was engaged in identifying dysregulated metabolic peaks from liquid chromatography mass spectrometry data sets, to address the issue retention time alignment they developed the first algorithm that allowed for the nonlinear alignment of metabolomics data called XCMS. [9] [38]
From the early 2000s [39] [12] to the present, the Siuzdak lab created and has been expanding the tandem mass spectrometry database known as METLIN. METLIN is made up solely of experimental data generated from high resolution tandem mass spectrometry instrumentation, all of the data is derived from molecular standards. METLIN (as of August 2022) has over 870,000 molecular standards with experimental tandem mass spectrometry data. [14] [13] [40] METLIN is unique with respect to its size, as other databases are over an order of magnitude smaller, [13] and it is also unique because all of METLIN's tandem mass spectrometry data has been systematically generated at multiple collision energies and in positive and negative ionization modes.
In 2020, the Siuzdak lab building off their work with Xavi Domingo [41] and METLIN, [12] [39] developed Enhanced In-Source Fragmentation/Annotation (EISA) [27] to facilitate the fragmentation, identification, and quantification (via Q-MRM) [28] [42] of molecules without the use of tandem mass spectrometry.
Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a mass spectrum, a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used in many different fields and is applied to pure samples as well as complex mixtures.
Tandem mass spectrometry, also known as MS/MS or MS2, is a technique in instrumental analysis where two or more stages of analysis using one or more mass analyzer are performed with an additional reaction step in between these analyses to increase their abilities to analyse chemical samples. A common use of tandem MS is the analysis of biomolecules, such as proteins and peptides.
Metabolomics is the scientific study of chemical processes involving metabolites, the small molecule substrates, intermediates, and products of cell metabolism. Specifically, metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind", the study of their small-molecule metabolite profiles. The metabolome represents the complete set of metabolites in a biological cell, tissue, organ, or organism, which are the end products of cellular processes. Messenger RNA (mRNA), gene expression data, and proteomic analyses reveal the set of gene products being produced in the cell, data that represents one aspect of cellular function. Conversely, metabolic profiling can give an instantaneous snapshot of the physiology of that cell, and thus, metabolomics provides a direct "functional readout of the physiological state" of an organism. There are indeed quantifiable correlations between the metabolome and the other cellular ensembles, which can be used to predict metabolite abundances in biological samples from, for example mRNA abundances. One of the ultimate challenges of systems biology is to integrate metabolomics with all other -omics information to provide a better understanding of cellular biology.
The metabolome refers to the complete set of small-molecule chemicals found within a biological sample. The biological sample can be a cell, a cellular organelle, an organ, a tissue, a tissue extract, a biofluid or an entire organism. The small molecule chemicals found in a given metabolome may include both endogenous metabolites that are naturally produced by an organism as well as exogenous chemicals that are not naturally produced by an organism.
Protein mass spectrometry refers to the application of mass spectrometry to the study of proteins. Mass spectrometry is an important method for the accurate mass determination and characterization of proteins, and a variety of methods and instrumentations have been developed for its many uses. Its applications include the identification of proteins and their post-translational modifications, the elucidation of protein complexes, their subunits and functional interactions, as well as the global measurement of proteins in proteomics. It can also be used to localize proteins to the various organelles, and determine the interactions between different proteins as well as with membrane lipids.
Desorption electrospray ionization (DESI) is an ambient ionization technique that can be coupled to mass spectrometry (MS) for chemical analysis of samples at atmospheric conditions. Coupled ionization sources-MS systems are popular in chemical analysis because the individual capabilities of various sources combined with different MS systems allow for chemical determinations of samples. DESI employs a fast-moving charged solvent stream, at an angle relative to the sample surface, to extract analytes from the surfaces and propel the secondary ions toward the mass analyzer. This tandem technique can be used to analyze forensics analyses, pharmaceuticals, plant tissues, fruits, intact biological tissues, enzyme-substrate complexes, metabolites and polymers. Therefore, DESI-MS may be applied in a wide variety of sectors including food and drug administration, pharmaceuticals, environmental monitoring, and biotechnology.
Matrix-assisted laser desorption electrospray ionization (MALDESI) was first introduced in 2006 as a novel ambient ionization technique which combines the benefits of electrospray ionization (ESI) and matrix-assisted laser desorption/ionization (MALDI). An infrared (IR) or ultraviolet (UV) laser can be utilized in MALDESI to resonantly excite an endogenous or exogenous matrix. The term 'matrix' refers to any molecule that is present in large excess and absorbs the energy of the laser, thus facilitating desorption of analyte molecules. The original MALDESI design was implemented using common organic matrices, similar to those used in MALDI, along with a UV laser. The current MALDESI source employs endogenous water or a thin layer of exogenously deposited ice as the energy-absorbing matrix where O-H symmetric and asymmetric stretching bonds are resonantly excited by a mid-IR laser.
Ambient ionization is a form of ionization in which ions are formed in an ion source outside the mass spectrometer without sample preparation or separation. Ions can be formed by extraction into charged electrospray droplets, thermally desorbed and ionized by chemical ionization, or laser desorbed or ablated and post-ionized before they enter the mass spectrometer.
In mass spectrometry, fragmentation is the dissociation of energetically unstable molecular ions formed from passing the molecules mass spectrum. These reactions are well documented over the decades and fragmentation patterns are useful to determine the molar weight and structural information of unknown molecules. Fragmentation that occurs in tandem mass spectrometry experiments has been a recent focus of research, because this data helps facilitate the identification of molecules.
The METLIN Metabolite and Chemical Entity Database is the largest repository of experimental tandem mass spectrometry and neutral loss data acquired from standards. The tandem mass spectrometry data on over 930,000 molecular standards is provided to facilitate the identification of chemical entities from tandem mass spectrometry experiments. In addition to the identification of known molecules, it is also useful for identifying unknowns using its similarity searching technology. All tandem mass spectrometry data comes from the experimental analysis of standards at multiple collision energies and in both positive and negative ionization modes.
Laser ablation electrospray ionization (LAESI) is an ambient ionization method for mass spectrometry that combines laser ablation from a mid-infrared (mid-IR) laser with a secondary electrospray ionization (ESI) process. The mid-IR laser is used to generate gas phase particles which are then ionized through interactions with charged droplets from the ESI source. LAESI was developed in Professor Akos Vertes lab by Peter Nemes in 2007 and it was marketed commercially by Protea Biosciences, Inc until 2017. Fiber-LAESI for single-cell analysis approach was developed by Bindesh Shrestha in Professor Vertes lab in 2009. LAESI is a novel ionization source for mass spectrometry (MS) that has been used to perform MS imaging of plants, tissues, cell pellets, and even single cells. In addition, LAESI has been used to analyze historic documents and untreated biofluids such as urine and blood. The technique of LAESI is performed at atmospheric pressure and therefore overcomes many of the obstacles of traditional MS techniques, including extensive and invasive sample preparation steps and the use of high vacuum. Because molecules and aerosols are ionized by interacting with an electrospray plume, LAESI's ionization mechanism is similar to SESI and EESI techniques.
Surface-assisted laser desorption/ionization (SALDI) is a soft laser desorption technique used for mass spectrometry analysis of biomolecules, polymers, and small organic molecules. In its first embodiment Koichi Tanaka used a cobalt/glycerol liquid matrix and subsequent applications included a graphite/glycerol liquid matrix as well as a solid surface of porous silicon. The porous silicon represents the first matrix-free SALDI surface analysis allowing for facile detection of intact molecular ions, these porous silicon surfaces also facilitated the analysis of small molecules at the yoctomole level. At present laser desorption/ionization methods using other inorganic matrices such as nanomaterials are often regarded as SALDI variants. As an example, silicon nanowires as well as Titania nanotube arrays (NTA) have been used as substrates to detect small molecules. SALDI is used to detect proteins and protein-protein complexes. A related method named "ambient SALDI" - which is a combination of conventional SALDI with ambient mass spectrometry incorporating the direct analysis real time (DART) ion source has also been demonstrated. SALDI is considered one of the most important techniques in MS and has many applications.
In the field of cellular biology, single-cell analysis and subcellular analysis is the study of genomics, transcriptomics, proteomics, metabolomics and cell–cell interactions at the single cell level. The concept of single-cell analysis originated in the 1970s. Before the discovery of heterogeneity, single-cell analysis mainly referred to the analysis or manipulation of an individual cell in a bulk population of cells at a particular condition using optical or electronic microscope. To date, due to the heterogeneity seen in both eukaryotic and prokaryotic cell populations, analyzing a single cell makes it possible to discover mechanisms not seen when studying a bulk population of cells. Technologies such as fluorescence-activated cell sorting (FACS) allow the precise isolation of selected single cells from complex samples, while high throughput single cell partitioning technologies, enable the simultaneous molecular analysis of hundreds or thousands of single unsorted cells; this is particularly useful for the analysis of transcriptome variation in genotypically identical cells, allowing the definition of otherwise undetectable cell subtypes. The development of new technologies is increasing our ability to analyze the genome and transcriptome of single cells, as well as to quantify their proteome and metabolome. Mass spectrometry techniques have become important analytical tools for proteomic and metabolomic analysis of single cells. Recent advances have enabled quantifying thousands of protein across hundreds of single cells, and thus make possible new types of analysis. In situ sequencing and fluorescence in situ hybridization (FISH) do not require that cells be isolated and are increasingly being used for analysis of tissues.
Desorption/ionization on silicon (DIOS) is a soft laser desorption method used to generate gas-phase ions for mass spectrometry analysis. DIOS is considered the first surface-based surface-assisted laser desorption/ionization (SALDI-MS) approach. Prior approaches were accomplished using nanoparticles in a matrix of glycerol, while DIOS is a matrix-free technique in which a sample is deposited on a nanostructured surface and the sample desorbed directly from the nanostructured surface through the adsorption of laser light energy. DIOS has been used to analyze organic molecules, metabolites, biomolecules and peptides, and, ultimately, to image tissues and cells.
Exometabolomics, also known as 'metabolic footprinting', is the study of extracellular metabolites and is a sub-field of metabolomics.
Phytosphingosine is a sphingoid base, a fundamental building block of more complex sphingolipids. It is abundant in plants and fungi and present in animals. Phytosphingosine has also been found to have interesting T-cell related anti-inflammatory properties in models of inflammatory bowel disease.
Secondary electro-spray ionization (SESI) is an ambient ionization technique for the analysis of trace concentrations of vapors, where a nano-electrospray produces charging agents that collide with the analyte molecules directly in gas-phase. In the subsequent reaction, the charge is transferred and vapors get ionized, most molecules get protonated and deprotonated. SESI works in combination with mass spectrometry or ion-mobility spectrometry.
XCMS Online is a cloud version of the original eXtensible Computational Mass Spectrometry (XCMS) technology, created by the Siuzdak Lab at Scripps Research. XCMS introduced the concept of nonlinear retention time alignment that allowed for the statistical assessment of the detected peaks across LCMS and GCMS datasets. XCMS Online was designed to facilitate XCMS analyses through a cloud portal and as a more straightforward way to analyze, visualize and share untargeted metabolomic data. Further to this, the combination of XCMS and METLIN allows for the identification of known molecules using METLIN's tandem mass spectrometry data, and enables the identification of unknown via similarity searching of tandem mass spectrometry data. XCMS Online has also become a systems biology tool for integrating different omic data sets. As of January 2021, the XCMSOnline - METLIN platform has over 44,000 registered users. XCMS - METLIN was recognized in 2023 as the year's top analytical innovation.
Gunda Köllensperger is an Austrian chemist and professor of chemistry at the University of Vienna. She investigates metallobiomolecules and drugs using inductively coupled plasma mass spectrometry. She was awarded the 2023 Houska Prize for her prize in Analytical Chemistry.
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