# Volumetric spatial-genetic imaging with DNA microscopy

> **NIH NIH R35** · UNIVERSITY OF CHICAGO · 2024 · $410,000

## Abstract

Project Summary/Abstract
Adaptive immune response, brain development, and tumor progression all display physiology that
depends on somatic mutations and genomic rearrangements among interacting cells. There is
currently no widely-available tool to capture nucleotide-level variation in a tissue’s three-
dimensional context. In my lab, we are developing spatial-genetic technologies to bridge this
major technological gap.
DNA microscopy, an imaging modality that I developed for generating spatial-genetic maps of
tissue de novo (Weinstein, Regev, Zhang, Cell 2019) provides a critical foundation for this work.
DNA microscopy encodes the spatial positions and nucleotide-level differences of cells into the
DNA products of a stand-alone chemical reaction. The technology operates by first tagging
individual DNA and RNA molecules with unique DNA barcodes, and then turning these barcoded
molecules into an intercommunicating network: linking barcodes to one another at rates that
depend on the distance between the original molecules. In doing so, DNA microscopy uses DNA
as an imaging medium, effectively imaging a specimen from the “inside-out”.
My lab’s research has two thrusts. The first of these is aimed at exploiting the fact that DNA
microscopy image-capture is intrinsically volumetric, and applying it to deep-tissue three-
dimensional spatial-genetic imaging. The second thrust of our research is aimed at using the
phylogenetic relationships encoded into the DNA of proliferating cells, via genomic mutations and
other forms of stochastic genomic reorganization, in order to ultimately decode from their
genomes information about cellular dynamics through time. Our goal is to use DNA microscopy’s
capability to jointly resolve cellular positions and cell clonal relationships to reconstruct their
spatial and temporal dynamics in model organism development. We further aim to apply this
framework to deepen our understanding of genomic variability in tumors and immune cells in
mammalian tissue. In this proposal, I describe our plan to achieve both of these goals, and to
establish a foundation for DNA microscopy to be deployed as a critical tool for spatial-genetic
imaging in both basic biology and pathology.

## Key facts

- **NIH application ID:** 10908408
- **Project number:** 5R35GM143017-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Joshua Weinstein
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2021-09-22 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908408

## Citation

> US National Institutes of Health, RePORTER application 10908408, Volumetric spatial-genetic imaging with DNA microscopy (5R35GM143017-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10908408. Licensed CC0.

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