Exploring the Next Frontier: Spatial Proximity Sequencing

We wanted to highlight a paper that takes spatial biology to the next level: measuring not just where proteins are, but which proteins are physically interacting in tissue.

The Problem

Spatial Biology tells us about protein abundance and location, but proteins rarely act alone. Understanding which proteins are actively forming complexes—and where this happens in tissue—has required separate, low-throughput assays. As the field evolves from Genomics → Proteomics → Spatial Biology, the next frontier is capturing the spatial context of protein-protein interactions.

The evolution of biological analysis: from Genomics to Spatial Proximity

The Solution

Sprox-seq (Spatial Proximity-Sequencing) builds on the team's earlier Prox-seq method, combining proximity ligation with a spatial platform. Antibody-oligo conjugate pairs form PLA products only when their target proteins are physically close (~50 nm), enabling direct detection of protein complexes alongside mRNA, all with spatial coordinates preserved.

Key Achievements

• Profiled 32 proteins, 528 pairwise protein interactions, and thousands of mRNAs across human tonsil germinal centers
• Protein interaction mapping revealed much higher complexity in the Light zone than RNA-based analysis alone
• Developmental trajectories inferred from protein interactions uncovered a B cell maturation pathway distinct from that inferred by RNA
• Captured B cell–Follicular Dendritic Cell interactions mediated by the VLA-4–VCAM1 complex in situ

How Were the AOCs Designed?

Notably, the team designed their own custom antibody panel using their own antibody-oligo conjugates rather than relying solely on supplier content, demonstrating the flexibility researchers need when pushing beyond standard spatial workflows.

What Will It Take for Widespread Adoption?

The technology elegantly demonstrates that spatial proximity is information-rich and biologically distinct from gene expression data. But scaling these approaches will require:

1. Panels of AOCs for proximity detection
2. Compatibility with various spatial platforms
3. Broad availability of conjugates that researchers can customize without starting from scratch

The focus of AbOliGo is to make AOCs accessible to all, thus allowing spatial proximity mapping to move from specialized applications to routine tissue analysis.

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