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2022 SUMS-RAS Speakers

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 MASS SPEC: THE VOYAGE HOME

Wednesday November 16, 2022, 9 am - noon Pacific Time

 

Dr. Chris Lock
Clinical Associate Professor, Multiple Sclerosis & Neuroimmunology, Dept. of Neurology, Stanford University

Exhaled Breath Analysis for Metabolic Profiling, Drug Levels, and Biomarker Discovery

Dr Chris Lock

Breath is a sign which has long been recognized at the bedside in clinical medicine in conditions such as diabetic ketoacidosis, liver failure, chronic renal disease, and some inborn errors of metabolism. The Greek physician Hippocrates (460-370 BCE) first described fetor oris and fetor hepaticus. The distinctive breath signatures in these conditions are the result of specific volatile organic compounds (VOCs). VOCs are products of endogenous biochemical processes and so enable monitoring of metabolic activity within the body. VOCs are carried from the body to the lungs by the blood, and appear in exhaled breath with concentrations ranging from parts per million (ppm) to parts per trillion (ppt) by volume.

Breath testing is non-invasive and highly sensitive, and repeated sampling is possible. Linus Pauling, a former Stanford professor and Nobel laureate, first reported capillary gas chromatographic analysis of breath in 1972. There has been a sharp rise in publications on breath-based VOC analysis in recent years. The technology has great promise but has been limited by mostly small studies utilizing different methodologies. Current issues are online versus offline sampling, standardization of breath collection, sample storage, quantification, quality control, analytical and statistical issues, study design, and validation. Investigators are attempting to standardize pipelines and workflows and to harmonize data.

Bio: Dr. Chris Lock was designed in England, and manufactured in Pontiac Michigan. He returned to England for school, attending King’s College London and Westminster Hospital Medical School. He then worked at King’s College Hospital and Imperial Cancer Research Fund laboratories (now Cancer Research UK), before re-crossing the pond to Stanford for a neurology residency, then a fellowship with Dr. Steinman. A period with Roche Bioscience, then clinical practice, and a stint at a startup followed, before returning to Stanford in 2015.

 

Dr. Yuqin Dai
Director, Metabolomics Knowledge Center, Sarafan ChEM-H, Stanford University

Metabolomics Knowledge Center: Open Access LC/MS Facility To Support Life Science Research

Dr Yuqin Dai

Metabolomics Knowledge Center is an open access LC/MS shared facility which aims to provide scientific expertise, LC/MS instrumentation, hands-on trainings and lead collaborations to support life science research within Stanford community. In this presentation, I will briefly introduce the Metabolomics Knowledge Center and its operational model and discuss some challenges and benefits of running an open access shared LC/MS facility. I will also discuss a collaboration project on Small Cell Lung Cancer (SCLC) metabolomics to illustrate the capabilities of the Metabolomics Knowledge Center and how we leverage LC/MS technologies to investigate metabolic heterogeneity and vulnerabilities within SCLC tumors. Metabolomics results help us understand the underlying mechanisms driving SCLC, which will facilitate the development of new therapeutic strategies.

Bio: Dr. Yuqin Dai is the Director of the Metabolomics Knowledge Center at Stanford Sarafan ChEM-H. In this role, she mangers daily operation and growth of the Metabolomics Knowledge Center, provides strategic vision and mentorship in the development of new LC/MS analytical methodologies for metabolomics research, She also collaborates with faculty in the development and execution of experiments aimed at measuring small molecule drug candidates, endogenous and exogenous metabolites in a variety of biomedical R&D contexts.  Dr. Dai came to Sarafan ChEM-H with 20 years of research, marketing and managerial experiences across biotech/pharma and analytical instrument industries. Prior to joining Sarafan ChEM-H in January of 2020, Dr. Dai worked at Agilent managing strategic collaborations with key opinion leaders in academia and industry for metabolomics research, driving new application marketing opportunities, and developing differential solutions to support new LC/MS and automation product introductions. Before Agilent, Dr. Dai led bioanalytical R&D teams to support drug discovery and development programs at biotech/pharma companies.

 

Dr. Ruth Huttenhain
Incoming Assistant Professor, Dept. of Molecular & Cellular Physiology, Stanford University

Mapping the Diversity in Spatiotemporal Regulation of G Protein-Coupled Receptors

Dr Ruth Huttenhain

G protein-coupled receptors (GPCRs) regulate diverse physiological processes in response to hormones, neurotransmitters, odorants, and light, making these receptors drug targets for many diseases. Despite their relevance, our understanding of their signaling is mostly limited to known signal transducers, such as heterotrimeric G proteins and Arrestins, and second messengers. These are however insufficient to explain the diverse physiological effects mediated by GPCRs, suggesting additional specialization on the cellular level. Here, we leverage a quantitative proteomics strategy for a diverse set of clinically relevant GPCRs to generate the first systematic, time-resolved map of their cellular response to activation in living cells.

Specifically, we used our recently developed proximity biotin labeling method based on the engineered peroxidase APEX combined with quantitative proteomics (GPCR-APEX-MS) for a panel of eleven GPCRs expressed along the pain pathways. Taking snapshots of their proximal proteome over a time course of activation, we demonstrated that GPCR-APEX-MS has the capacity to simultaneously capture interaction networks and cellular location of the activated receptors with high temporal resolution.

Our spatiotemporal GPCR map revealed (1) a striking diversity in receptor localization and trafficking of the pain-related GPCRs and (2) a combined interaction network containing shared and receptor-specific interactors. For example, we discovered a novel interaction specific for the RF-amide receptor NPFFR1 with the CUL1FBXW11 E3 ligase complex. We found that this interaction depends on a phosphodegron in the C-terminal tail of NPFFR1 which becomes phosphorylated by G protein-coupled receptor kinases (GRKs) upon activation. Both mutation of the phosphodegron and inhibition of GRKs stabilized the receptor, indicating that CUL1FBXW11 may be involved in ubiquitination and degradation of the activated NPFFR1.

These results (1) exemplify the power of quantitative proteomics to illuminate GPCR biology and (2) suggest that cellular compartmentalization of signaling and receptor specific interactions might contribute to the diversity of GPCR cellular responses.


Bio: Ruth obtained her Ph.D. in Systems Biology from ETH Zurich, Switzerland, where she worked with Ruedi Aebersold, Ph.D, to develop a novel, targeted proteomics strategy for sensitive and reproducible quantification of proteins across large sample cohorts. Supported by the Swiss National Science and the Human Frontiers Science Foundation, Ruth performed her postdoctoral work with Nevan Krogan, Ph.D., at the University of California, San Francisco (UCSF). During her postdoc, Ruth studied protein network dynamics in the context of HIV infection, which led to the discovery of the ARIH2 as a novel HIV-dependency factor. She also pioneered the first proteomics approach that can resolve protein interaction networks simultaneously with temporal and spatial resolution. Applying this approach to study dynamics of protein networks engaged by ligand-activated GPCRs led to the discovery of a previously unrecognized ubiquitin network regulating opioid receptor function. After her postdoc Ruth continued at UCSF as an Assistant Adjunct Professor with a research focus on how GPCRs decode extracellular cues into dynamic and context-specific cellular signaling networks to elicit diverse physiologic responses, a research direction that she will further explore in her lab at Stanford. She will exploit quantitative proteomics to capture the spatiotemporal organization of GPCR signaling networks combined with functional genomics to study their impact on physiology.

 

Dr. Christie Jilly-Rehak
Research Scientist/Lab Manager, Dept. of Geological Sciences and Stanford Nano Shared Facilities (SNSF)

Dynamic SIMS at Stanford: Applications in Secondary Ion Mass Spectrometry using the NanoSIMS and the SHRIMP-RG Instruments

Secondary Ion Mass Spectrometry is a valuable tool for characterizing the isotopic and/or elemental composition of a solid surface. In this talk I will discuss two dynamic SIMS instruments that I manage at Stanford and their research applications: The Cameca NanoSIMS 50L and the SHRIMP-RG Ion Microprobe. Both instruments are used to sputter a surface with a primary ion beam (either Cs or O) and measure the emitted secondary ions by magnetic-sector mass spectrometry. The NanoSIMS specializes in high spatial resolution ion imaging (down to 50nm per pixel) at high mass resolution (up to ~15,000 M/ΔM), with ~ppm sensitivity. Our NanoSIMS user base spans 12 departments, with diverse research applications ranging from ion imaging of 2H, 13C, 15N labeling in cells, to high precision 34S/32S isotopes in gold-bearing ore deposits, to depth profiling of Li-ion battery materials. In contrast, the SHRIMP-RG ion microprobe specializes in high precision isotopic and trace element analysis at very high mass resolution (capable of up to 30,000 M/ΔM), with sensitivity in the ppm and even ~ppb range for some isotopes. The majority of the SHRIMP-RG usage is for radiometric dating (such as U-Pb) and trace element analyses of terrestrial and extraterrestrial minerals.

Bio: Christie is a research scientist specializing in secondary ion mass spectroscopy (SIMS).  She serves as a lab manager for the Cameca NanoSIMS 50L instrument in the Stanford Nano Shared Facilities, as well as the SHRIMP-RG secondary ion mass spectrometer in the Geological Sciences department. Prior to Stanford, Christie received her Ph.D. in Geology and Geophysics from the University of Hawaii at Manoa, utilizing their Cameca 1280 IMS ion microprobe for isotopic analyses of meteoritic materials, as well as SEM/EDS and EPMA for sample characterization. She completed a postdoc at UC Berkeley Space Sciences Laboratory, where she gained experience in numerous other microanalytical techniques, including FIB, TEM, and synchrotron XANES. Her primary research interests include stable isotope geochemistry and radiometric dating of terrestrial and extraterrestrial material.

 

Dr. Parag Mallick
Associate Professor, Canary Center for Cancer Early Detection, Stanford University

Quantifying the Reproducibility of Proteogenomic Analyses using a Semantically Aware Discovery Engine

Initiatives like the Clinical Proteomic Tumor Analysis Consortium (CPTAC) have been launched in the past decade to examine the multi-omic relationships that drive cancer behavior. Beyond uncovering novel subtypes these studies have revealed the incredibly complex relationships that exist between genome, transcriptome and proteome. Unfortunately the analysis of multi-omics data is exponentially more challenging that single-ome analysis. Seemingly subtle changes in workflow can have dramatic impacts on findings. Building on top of an intelligent semantic workflow system, we captured the analytic methods of key proteogenomic papers as workflows and executed them systematically against diverse large multi-omics datasets. These studies revealed the fragility of multi-omic analyses. At the lowest levels (peptides identified), even trivially small changes had massive implications in what peptides or proteins were identified. Interestingly, higher-order findings such as patient strata were invariant to many perturbations. Ultimately, these studies suggest that even computational analyses, which we think of as highly systematic and reproducible, may be subject to many of the same issues as experimental studies.

Bio: Dr. Parag Mallick is an Associate Professor at Stanford University. Originally trained as an engineer and biochemist, his research spans proteomics, computational and experimental systems biology, cancer biology and nanotechnology. Dr. Mallick received his B.S. in Computer Science from Washington University in St. Louis. He then obtained his Ph.D. from UCLA in Chemistry & Biochemistry, where he worked with Dr. David Eisenberg. He completed his post-doctoral studies at The Institute for Systems Biology with Dr. Ruedi Aebersold. Dr. Mallick’s group has been pioneering systems-biology approaches towards understanding disease mechanisms, discovering biomarkers and enabling personalized medicine. Most recently, his group has been developing model-based and physics-based approaches to machine learning that enable learning over domains that span a wide range of time and length scales. Dr. Mallick has over 100 publications and holds patents in the fields of artificial intelligence, proteomics technology, biomarker development, and nanotechnology. Additionally, he is a co-founder of Nautilus Biotechnology and advisor to numerous biotechnology and diagnostics companies.

 

Dr. Sharon Pitteri
Associate Professor, Dept. of Radiology, Stanford University

Intact Glycopeptide Analysis of Human Tissue and Fluid Samples for Cancer Detection

Dr Sharon Pitteri

Bio: Dr. Sharon Pitteri is an Associate Professor in the Department of Radiology at the Stanford University School of Medicine.  She is a member of the Canary Center at Stanford for Cancer Early Detection, Stanford Cancer Institute, Stanford Bio-X Program, and Stanford Cancer Biology Program.  She received her bachelor’s degree in Chemistry from Carleton College and her PhD in Chemistry from Purdue University.  Dr. Pitteri did her postdoctoral research in Molecular Diagnostics at the Fred Hutchinson Cancer Research Center.  Her current research focuses on the identification of proteins and other molecules that are indicative of early stage and/or aggressive cancer in blood, tissue, and proximal fluids.  Her lab develops and applies mass spectrometry-based methods to study protein glycosylation in order to better understand cancer biology and ultimately improve cancer diagnosis.  She is the recipient of numerous awards including the American Society for Mass Spectrometry Research Award, California Breast Cancer Research Program Innovative Development and Exploratory Award, Stanford McCormick Faculty Award, and Department of Defense Breast Cancer Breakthrough Award.  She is a member of the NIH Glycoscience Common Fund Program and the NCI Alliance of Glycobiologists for Cancer Research.  She is currently serving as Treasurer of the American Society for Mass Spectrometry and Vice Chair of the California Breast Cancer Research Council.

 

Dr. Karrie Weaver

Research Scientist and Technical Director, SIGMA Facility, Dept. of Earth Systems Science, Stanford Doerr School of Sustainability

Mass Spectrometry in Space and Time: Using ICPMS to Characterize Materials Across Disciplines and Through the Ages

Bio: Karrie specializes in high precision isotopic composition and concentration determinations in earth materials, environmental monitoring samples, and engineered materials. Her background in mass spectrometry and technique development allows her to work with researchers across many disciplines to apply new methods of material characterization to challenging analytical problems.

 

Dr. Shou-Ling Xu
PI, Director of Carnegie Mass Spectrometry Facility, Dept. of Plant Biology, Carnegie Institution for Science

Making Invisible Visible

Bio: Dr. Xu received her ph.D in Biology with Dr. Joseph Kieber from the University of North Carolina at Chapel Hill. She did her joint postdoc work with Dr. Zhiyong Wang at Carnegie and Dr. Alma Burlingame, at UCSF mass spectrometry facility, focusing on characterizing protein complexes and protein modifications using proteomics tools. She then did a one-year postdoc at ThermoFisher Scientific proteomics marketing, focusing on targeted quantification and instrumentation. In 2017, Dr. Xu was appointed as a PI and director of Carnegie mass spectrometry facility at Carnegie Institution. The MS facility has been collaborating with labs within Carnegie and multiple biology labs at Stanford on deploying proteomics approaches to study biological questions. Her lab deploys various state-of-art mass spectrometry tools, including proximity-labeling mass spectrometry and cross-linking mass spectrometry to study nutrient sensing and alternative splicing machinery.