A High Throughput and High Sensitivity Mass Spectrometer for Proteomics Studies on Human Diseases - PROJECT SUMMARY We request funds for a novel mass spectrometer, the Orbitrap Astral, to be located at the Massachusetts General Hospital (MGH) and to be used for proteomics studies focusing on cancer and Alzheimer’s disease research. The proteome is defined as the entirety of all proteins in biological systems, and it encloses many different aspects such as (i) protein expression and concentration, (ii) posttranslational protein modification such as phosphorylation, acetylation, methylation, and ubiquitination, (iii) protein interactions, (iv) intracellular protein localization, (v) enzyme activities, and many more. Most of this information can only be accessed through directly measuring the proteome, and this is enabled through proteomics technology with mass spectrometry being the most important tool. Nevertheless, proteomics usage is small when compared to the wide usage of genomics technologies, and we believe this hinders progress in a better understanding of complex diseases such as cancer and neurodegenerative disorders and ultimately a better treatment of these diseases. So why is proteomics not more broadly used in disease research and has not been incorporated into the diagnostics in clinical treatment? We believe two major reasons are a lack of sensitivity when compared to genomics technologies and a lack of sample throughput, which impacts studying complex diseases and results in high costs of proteome analysis. Both hurdles were addressed by the development of a novel mass spectrometer by Thermo Fisher Scientific, the Orbitrap Astral, which includes a new extremely fast mass analyzer with unprecedented sensitivity. This high-resolution accurate-mass (HRAM) analyzer enables extreme scan rates (200 Hz) at single ion detection limits and provides unprecedented performance across all current mass spectrometry-based proteomics approaches including isobaric labeling-based multiplexed quantification and data-independent acquisition (DIA). First data generated with the instrument show that the Orbitrap Astral is a game changer for proteomics that will redefine what can be achieved in the field. It outperforms existing mass spectrometers by several folds in mapping cell line and tissue proteomes, plasma proteomes, phosphoproteomes, and proteomes of low sample inputs (single-cell proteomics). The instrument will benefit the research of 13 projects (9 major and 4 minor users) in cancer and Alzheimer’s disease research and will be available to NIH-funded researchers beyond the MGH in Boston and nationwide. It will be supported by all levels of institutional levels, including the MGH Cancer Center, and the MGH Executive Committee for Research. Institutional funds are committed to installing, maintaining, and running the platform. We believe that the Orbitrap Astral will drive new discoveries in cancer and Alzheimer’s research and beyond including the identification of disease biomarkers for detection and monitoring progress, for identifying cancer vulnerabilities including combination treatment targets for overcoming treatment resistance, and as a platform to develop even faster and deeper methods for exploring disease proteomes.
