Breakthroughs in spatial mapping of biological systems
Understanding biological systems at a high resolution, both structurally and functionally, has been a long-standing goal in life sciences research. While traditional biological assays provide insights into average characteristics of cell populations, spatial information on the molecular makeup and interactions within heterogeneous tissues is lost. Recent technological advances now enable mapping gene expression, protein localization and other molecular qualities at microscopic scales within intact tissues and organs. These spatially resolved “omics” approaches, collectively referred to as spatial omics, are revolutionizing our understanding of biological complexity within native microenvironments.
Mapping the transcriptional landscape
One of the early successes in spatial omics was achieved through multiplexed fluorescence in situ hybridization (FISH), which allows simultaneous detection of dozens of mRNA targets within intact tissues or cells at single-molecule resolution. By mapping expression patterns of many genes together, researchers were able to unravel complex cell-type compositions and transcriptional programs running across brain and lung tissues. However, FISH approaches are limited by the number of targets that can be profiled in a single experiment.
Massively multiplexed spatial transcriptomics techniques such as the 10x Genomics Visium platform have pushed this boundary by employing RNA-based combinatorial barcoding to profile thousands of genes simultaneously from cryosectioned tissues. In a recent application of Visium, researchers mapped over 4000 genes across ninety distinct types of cells and uncovered novel transcription factors defining cell identities in the mouse cortex. Spatial transcriptomics experiments are also providing insights into tissue-scale gene expression gradients, cytokine-mediated immune cell communication networks in lymph nodes, and molecular insights into disease contexts such as cancer.
Going beyond genes - mapping the proteome, epigenome and metabolome
While spatial transcriptomics is a powerful approach, mRNA levels do not perfectly reflect protein abundances or post-translational modifications. Fluorescent immunohistochemistry and multiplexed ion beam imaging (MIBI) have enabled high-dimensional profiling of dozens of protein markers within intact tissues and whole organ systems such as the mouse brain. Integrating spatial transcriptomics and protein imaging datasets provides a more comprehensive view of molecular organization and cell phenotypes in situ.
Epigenetic regulation through DNA methylation and histone modifications also plays a key role in controlling cell identity and function. Spatial assays like EpiTOF are now mapping histone modifications and DNA modifications across chromosomes at single-cell resolution within tissues. Metabolite imaging techniques based on mass spectrometry are unveiling spatial organizations of small molecule metabolites and fluxes within model organisms and human tumor specimens.
Towards comprehensive multi-omics mapping
The ultimate goal of spatial omics is to integrate diverse omics layers - genes, proteins, epigenomes, metabolomes - within the native spatial architecture of biological systems. Early attempts at multi-omics mapping include the combination of spatial transcriptomics with MIBI imaging on the same formalin-fixed paraffin embedded (FFPE) tissue sections. More advanced workflows are being developed to perform serial sectioning followed by alternative staining and imaging rounds to achieve deeper multi-omics profiling of individual cells and microenvironments at single-cell resolution. Simultaneous measurement of different omics layers from the same microscopic volume is key to unraveling complex mechanisms of biological organization and disease pathogenesis.
Clinical and therapeutic applications
With their ability to characterize disease states and drug responses at microscopic scales within intact tissues, spatial omics techniques are primed for significant impact on precision medicine. Spatial profiling of tumor biopsies can reveal novel subtypes and trajectories of cancer evolution, stratify disease subtypes for targeted therapies, and monitor treatment responses at the resolution of individual cells. Spatial transcriptomics is also providing insights into complex autoimmune and neurological disorders by mapping molecular changes accompanying disease progression across diverse cell types in affected tissues.
Future outlook
The field of spatial omics is rapidly evolving through major technological innovations that enable broader coverage of biological molecules, deeper multiplexing, higher resolutions, and larger sample throughput. Integration of spatial data with computational modeling is emerging as a promising avenue to simulate and predict emergent behaviors of biological systems. Widespread clinical applications in areas such as cancer diagnostics and monitoring treatment response will motivate further developments towards automated, routine analysis platforms. The comprehensive mapping of molecular organization within intact biological contexts promised by spatial omics holds potential to transform our understanding of physiology, development and disease in the years to come.
Get more insights on this topic :
