Scientists at the University of Chicago have introduced “volumetric DNA microscopy,” which has the potential to transform our understanding of biology by producing detailed, three-dimensional images of organisms at the molecular level. For the first time, this technology can provide a spatial map of gene expression for an entire organism.
[Image courtesy of Weinstein Lab, University of Chicago]
Traditional genetic sequencing provides valuable information about samples’ genetic makeup and activity. However, these methods fall short when revealing the precise location of genetic sequences within a sample and their relationships to other molecules. The innovative DNA microscopy developed at UChicago overcomes these limitations.
The technology tags individual DNA or RNA molecules and allows neighboring tags to interact. This interaction constructs a molecular network that encodes the relative positions of the molecules, effectively creating a spatial map of the genetic material.
“It’s a level of biology that no one has ever seen before,” said Joshua Weinstein, PhD, Assistant Professor of Medicine and Molecular Engineering at UChicago, who has dedicated over 12 years to developing DNA microscopy. Grants from the National Institutes of Health and the National Science Foundation have supported his work. “To be able to see that kind of a view of nature from within a specimen is exhilarating.”
In a recent paper published inNature Biotechnology, Weinstein and postdoctoral scholar Nianchao Qian showcased the technology’s capabilities by creating a complete DNA image of a zebrafish embryo, a widely used model organism in developmental and neurobiological research.
Unlike conventional microscopes, which rely on light and lenses, DNA microscopy constructs images by calculating molecule interactions. Short DNA sequence tags, called unique molecular identifiers (UMIs), are attached to DNA and RNA molecules within cells. These UMIs then replicate and initiate a chemical reaction that generates unique event identifiers (UEIs) specific to each pairing.
The frequency of UMI interactions reflects their spatial proximity: UMIs that are close together interact more frequently and produce more UEIs than those farther apart. Following DNA and RNA sequencing, a computational model analyzes the physical links between UMI tags to reconstruct their original locations, generating a spatial gene expression map.
Weinstein draws an analogy to cell phone data: “We can do this with cell phones and people, so why not do that with molecules and cells,” he said. “This turns the idea of imaging on its head. Rather than relying on an optical apparatus to shine light in, we can use biochemistry and DNA to form a massive network between molecules and encode their proximities to each other.”
This new imaging technique is particularly powerful because it doesn’t depend on prior knowledge of the genome or the specimen’s shape. One promising application is in cancer research, where DNA microscopy can map the tumor microenvironment and its interactions with the immune system. This insight could guide the development of more precise immunotherapies and personalized vaccines.
“This is the critical foundation for being able to have truly comprehensive information about the ensemble of unique cells within the lymphatic system or tumor tissue,” Weinstein noted. “There has still been this major gap in technology for allowing us to understand idiosyncratic tissue, and that’s what we’re trying to fill in here.”
The Damon Runyon Foundation and the Moore Foundation provided additional funding for the study, “Spatial-transcriptomic imaging of an intact organism using volumetric DNA microscopy.” The development and application of this technology promise to open new frontiers in biological research.