Spatial Delivery

GEN BiotechnologyVol. 2, No. 5 Guest Editorial: Spatial OmicsFree AccessSpatial DeliveryRong Fan and Fay LinRong Fan*Address correspondence to: Rong Fan E-mail Address: [email protected]Department of Biomedical Engineering, Yale University, New Haven, Connecticut, USA.Guest Editor, GEN Biotechnology.Search for more papers by this author and Fay Lin*Address correspondence to: Fay Lin E-mail Address: [email protected]Senior Editor, GEN Biotechnology.Search for more papers by this authorPublished Online:16 Oct 2023https://doi.org/10.1089/genbio.2023.29117.editorialAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Spatial omics enables the profiling of a variety of biomolecules with high spatial resolution across the central dogma of molecular biology directly in the natural tissue context. It has emerged as a powerful tool to analyze clinical samples for human biology research, therapeutic discovery, and translational medicine. As one of the fastest growing areas in the biotech industry, spatial omics is poised to drive the next biology revolution with broad impact across life science and medicine.In this debut special issue of GEN Biotechnology, we are delighted to feature a collection of spatial omics perspectives, reviews, and original research articles capturing the breadth of the field from cancer research to the newest advances in imaging methods.Lift OffThe historical roots of visualizing biological function date back 300 years with the invention of the compound microscope by Robert Hooke. Individual cells were seen for the first time in a plant leaf, and researchers could already visualize highly heterogeneous cell morphology implicated in distinct functions in various tissue regions. While the modern era of molecular and cell biology associates morphological heterogeneity with differential gene expression, it was the rise of single-cell genomewide gene expression measured by next-generation sequencing (NGS) platforms that allowed for detailed quantification of cellular heterogeneity in gene expression. Further breakthroughs in massively parallel single-cell sequencing via cellular barcoding enabled the gene expression profiling of thousands of single cells, thereby dissecting cell types and states in large cell populations. But despite these major breakthroughs in single-cell omics, analyzing cellular heterogeneity in the tissue context remained a challenge.Over the past decade, we have witnessed the exponential growth of an emerging field—spatial omics. The goal is to map genomewide biomolecular information pixel-by-pixel in undissociated tissue to yield a holistic view of cell type, state, and function in the native tissue context. Broadly speaking, there are two avenues to achieve this goal—one based on imaging, and the other based on NGS.Imaging-based spatial omicsAlthough single-molecule imaging and fluorescence in situ hybridization (FISH) are established techniques, it was not intuitive how to expand them to image genomewide expression. It was the conceptional breakthrough to combine FISH probes, as demonstrated in multiplexed error-robust fluorescence in situ hybridization (MERFISH) and sequential FISH, with repeated hybridization and imaging that eventually led to genomewide spatial gene expression profiling by single-molecule FISH.Spatial phenotyping at single-cell resolution has become valuable to analyze tumors and the tumor microenvironment (TME). While most high-plex spatial studies have focused on transcriptomic analysis (see the review article on page 384), researchers from Akoya Biosciences present a framework for single-cell spatial analysis of proteins to analyze head and neck squamous cell carcinomas, the seventh most common cancer (see on page 419). The authors state that this spatial mapping of the proteome in homeostasis and disease provides applications to identify novel biomarkers, disease stratification, and understand the basis of variable clinical responses. (For more news coverage on the latest advances in spatial omics and the TME, see the news feature by Sachin Rawat on page 342.)NGS-based spatial omicsA landmark paper published by Joakim Lundeberg and colleagues in 2016 in Science demonstrated the use of DNA microarrays (spot size 100 μm) to capture mRNA molecules released from a tissue section that was placed on the slide and permeabilized to allow mRNA molecules to escape. Then, reverse transcription on the slide generates spatially barcoded cDNA that can be pooled, amplified, and profiled using paired-end NGS to read spatially resolved unbiased genomewide gene expression spot-by-spot in a tissue section. This technology was commercialized by 10 × Genomics in 2019 as the Visium Spatial platform, resulting in rapid and wide-spread adoption in a variety of biological and biomedical fields.The cover of this issue, crafted by talented artist Mon Oo Yee, features one of the most-studied human organs, the brain, and illustrates how spatial omics provides a powerful tool to understand neurodegenerative disorders such as Alzheimer's disease (AD). On page 399, researchers from Johns Hopkins University present a roadmap for identifying spatially resolved transcriptional signatures associated with amyloid-beta pathology in postmortem brain tissue from AD patients. The authors state that their data analysis workflow, using the 10 × Visium Spatial Proteogenomics platform, represents a proof-of-principle for the power of multiomic profiling in spatial characterization of molecular dynamics associated with brain pathology.New DimensionsOver the past 3 years, the general foundational approach of barcoded solid-phase RNA capture for spatial transcriptomics profiling has been further improved to demonstrate subcellular spatial gene expression mapping (e.g., SeqScope, Stereo-seq, and Pixel-seq). Nevertheless, they all follow the same fundamental principles coined by Lundeberg as “barcoded solid surface for mRNA capture and spatial transcriptomics.” Since 2019, there has been a technically distinct, contrasting approach to spatial omics, one based on spatially defined delivery of DNA barcodes into a fixed and permeabilized tissue to perform deterministic barcoding in tissue for spatial omics sequencing (DBiT-seq). This approach turns out to be highly versatile, which not only demonstrated for the first time spatial multi-omics sequencing (transcriptome and proteins) but also has been further developed to enable spatially resolved epigenome sequencing (i.e., spatial-ATAC-seq and spatial-CUT&Tag) as well as spatial epigenome-transcriptome co-sequencing. This has opened an entirely new dimension in the field of spatial biology.Given the important role of gene expression profile to determine a cell type or state, spatial transcriptomics is largely synonymous with spatial gene expression mapping. But what is emerging beyond spatial gene expression represents the most exciting frontiers in this field. As noted above, DBiT is unique in its versatility, unlocking a whole new direction in spatial epigenomics. Recently, image-based methods such as MERFISH have also demonstrated targeted detection of epigenetic loci associated with specific histone markers.Spatial metabolomics is another branch that is poised to provide indispensable information regarding cellular function in relation to diet, aging, and disease. Mass spectrometry imaging allows for near single cell resolution profiling of metabolites such as lipidome in an unbiased manner to differentiate different lipid species. Optical chemical imaging including infrared and stimulated Raman scattering (SRS) imaging is unique in that it can detect select metabolites at an unprecedented subcellular or even nanometer-scale resolution, and it is nondestructive and label free.On page 435, researchers from Duke University present a label-free reflection-mode hyperspectral photoacoustic microscopy (RHS-PAM) system to overcome the limitations of conventional hyperspectral imaging methods, which predominantly rely on fluorescent signatures, limiting their application to nonfluorescent samples. The report illustrates the ability of RHS-PAM to utilize the optical absorption contrast of nucleic acids, proteins, hemoglobin, melanin, and lipids in an array of model organisms, including Caenorhabditis elegans, zebrafish, and mice. RHS-PAM may offer clinicians a more noninvasive method to obtain cellular-level spatial omics, thereby opening new doors to diagnostics and treatments.Back to spatial mapping of RNA molecules, the life of an RNA molecule is rich and dynamic, far beyond the capacity of spatial gene expression to reveal. Thus, researchers are still grappling with how to map RNA molecules at different stages of their life cycles, their splicing variants, their interaction with proteins, and the regulation mechanism of noncoding RNAs—these are all important questions in cellular and tissue biology. Finally, we would like to know how to map temporal dynamics of biomolecules and cells and how to map them in large 3D tissue structure at genome scale. These are the next frontiers of spatial omics, which may be on the horizon in the following years.Rounding out this special issue on spatial omics are two important Perspectives. On page 360, researchers from Yale describe key clinical applications of spatial omics technologies, such as retrieval of disease-related information in single samples and the development of personalized treatments. While technical and financial challenges still limit the deployment of these technologies in clinical laboratories, the potential for spatial omics to deepen pathologic analysis in human tissue sampling remains unfathomed. And on page 372, a team from Georgia Institute of Technology and Emory University describe the directions in spatial omics for organoid characterization. Through a case study using retinal organoids and native retinal tissues, the authors discuss how spatial omics can enhance the in situ study of single cells in organoids without expensive animal models.That's not all in this issue of GEN Biotechnology! We also have a fascinating interview with genome-editing pioneer Fyodor Urnov (page 347); a profile of Charles Zuker's new company Kallyope (page 338); a commentary from Sean Ekins on strategies for developing treatments for rare diseases (page 353); and a news feature on the promise of artificial intelligence in the field of protein design (page 333).We hope you enjoy this special issue on spatial omics, and we will continue to encourage submissions of groundbreaking studies showcasing and advancing this powerful technology. And look for the imminent announcement of our next special issue to be published in 2024—BIOTECHNOLOGY AND HEALTH DISPARITIES, assisted by guest editors Brian Aguado (University of California, San Diego), Karmella Haynes (Emory University), and Ana Maria Porras (University of Florida).Rong Fan, PhD (Yale University), served as guest editor for this special issue of GEN Biotechnology. Email: rong.fan@yale.eduFay Lin, PhD, is Senior Editor of GEN Biotechnology. Email: flin@liebertpub.comFiguresReferencesRelatedDetails Volume 2Issue 5Oct 2023 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Rong Fan and Fay Lin.Spatial Delivery.GEN Biotechnology.Oct 2023.331-332.http://doi.org/10.1089/genbio.2023.29117.editorialPublished in Volume: 2 Issue 5: October 16, 2023PDF download