Subcellular Co-Mapping of Gene Expression and Protein Histology
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Solution Overview
Problem
Existing spatially resolved transcriptomic technologies are incompatible with protein detection in the same tissue sections, limiting the resolution and accuracy in studying Alzheimer's disease pathology, particularly in mapping gene expression and protein histology in relation to amyloid plaques and tau tangles.
Innovation Solution
The STARmap Pro method enables high-resolution spatial transcriptomics with simultaneous protein localization in the same tissue section by using oligonucleotide probes for nucleic acid amplification and antibody binding to proteins, followed by imaging to map gene and protein expression at subcellular resolution.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If spatially resolved transcriptomic technologies are used, then spatial patterns of gene expression are preserved, but protein detection in the same tissue sections is incompatible
Solution Approach 1:
The patent combines spatial transcriptomics and protein histology detection into a single integrated workflow by performing both mRNA sequencing and protein immunostaining on the same tissue section. This merging of previously separate techniques enables simultaneous preservation of spatial patterns for both gene expression and protein localization, resolving the contradiction between measurement precision and adaptability.
Solution Approach 2:
The methodology creates a universal platform that can detect multiple types of biomolecules (mRNA and proteins) with the same spatial resolution on the same tissue section. This multi-functional approach allows the system to adapt to different detection needs while maintaining high spatial precision, thereby increasing versatility without sacrificing measurement precision.
2Adaptability or versatility
If adjacent-section strategy is used for protein staining, then some spatial information is preserved, but resolution and accuracy are limited
Solution Approach 1:
The patent extracts and removes the compromising factor of section thickness by performing all detections on an ultra-thin section (200 nm) rather than relying on adjacent thicker sections. This extraction of the problematic element enables both high spatial accuracy and versatile detection capability simultaneously, as the thin section allows precise localization without the resolution limitations of thicker adjacent sections.
3Device complexity
If standard imaging methods are used, then limited cell types can be identified, but molecular and cellular complexity cannot be uncovered
Solution Approach 1:
The patent introduces an intermediary approach by using a unified detection platform that processes multiple molecular targets (mRNA and proteins) through a single integrated workflow. This intermediary system bridges the gap between simple imaging methods and complex molecular analysis, enabling comprehensive uncovering of molecular complexity while maintaining methodological coherence and reducing information loss.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Provides a comprehensive molecular atlas of Alzheimer's disease pathophysiology, allowing for detailed analysis of cellular responses to amyloid plaques and tau aggregation, and identifying disease-associated pathways across diverse cell types.
Implementation Method 1
contacting the cell with one or more pairs of oligonucleotide probes, wherein each pair of oligonucleotide probes comprises a first oligonucleotide probe and a second oligonucleotide probe
Implementation Method 2
performing rolling circle amplification to amplify the circular oligonucleotide using the second oligonucleotide probe as a primer to produce one or more concatenated amplicons
Implementation Method 3
contacting the cell with one or more detecting agents, wherein each detecting agent binds to a protein of interest
Implementation Method 4
imaging the one or more concatenated amplicons embedded in the polymeric matrix and the one or more detecting agents embedded in the polymeric matrix to determine the location of the nucleic acids of interest and the proteins of interest within the cell
Data Source
Figure 1A
Figure 1B
Figure 1C~1D
AI summary
The present disclosure provides methods and systems for mapping gene and protein expression in a cell (i.e., mapping gene and protein expression within the same cell simultaneously). The present disclosure also provides methods for diagnosing a disease or disorder (e.g., a neurological disorder such as Alzheimer's disease) in a subject. Methods of screening for a candidate agent capable of modulating gene and/or protein expression are also provided by the present disclosure. The present disclosure also provides methods for treating a disease or disorder, such as Alzheimer's disease, in a subject in need thereof. A plurality of oligonucleotide probes, which may be useful for performing the methods described herein, are also described by the present disclosure, as well as kits comprising any of the oligonucleotide probes described herein. Additionally, the present disclosure provides methods, apparatuses, and non-transitory computer-readable storage media for identifying spatial variations of cell types in at least one image.