By Andrea McManus

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Biologists are always seeking cutting-edge technologies that enable them to make new discoveries. However, choosing the right technology can be a difficult journey for many organizations. Christina Baer, PhD, the Director of the Sanderson Center for Optical Experimentation (SCOPE) at the University of Massachusetts Medical School (UMMS) in Worcester, MA, is regularly on this quest.

As director of SCOPE, she must find the right technology that eliminates roadblocks for researchers. When presented with the opportunity in 2019 to apply for the Massachusetts Life Sciences Center’s (MLSC) Bits to Bytes Initiative grant, Baer wanted to bring state-of-the-art technology into her core.

In a collaboration with Dorothy Schafer, PhD, an associate professor at UMMS, the goal was to bring spatial genomics to the SCOPE. Spatial genomics allows for cells to be evaluated within their intact native tissue environment while quantifying gene expression and providing the location of RNA transcripts within single cells. Baer shared, “The exciting thing to me is that we can finally start to understand the cellular organization underlying what we’re observing in the tissue. We knew how monumentally transformative it was going to be for biology.”

Baer and Schafer performed a comprehensive review of the technologies available to ensure they chose the right one. As a neuroscientist, Shafer was aware of the multiplexed error robust in situ hybridization (MERFISH) method. After watching a seminar on MERFISH, she was hooked.

MERFISH is a powerful combination of microscopy and genomics based on single-molecule FISH (smFISH). Developed in the laboratory of Xiaowei Zhuang, PhD, Harvard University, it uses combinatorial labeling, sequential imaging, and error-robust barcoding to accurately image, quantify, and locate hundreds of gene targets within a single experiment.

According to Baer, “MERFISH is the first implementation of a spatial genomics technique that’s tissue wide, has subcellular resolution, and gives you that unique sensitivity. Being able to get down to 0.1 copies per cell is critical for looking at lower abundance genes.” She found that other approaches could not achieve the same sensitivity as MERFISH.

MERFISH results from mouse tissue.
Figure 1. Representative MERFISH results from mouse tissue. With a 130-probe library, different populations of cells in the mouse brain were successfully mapped. (A) Map of 31 distinct cell populations in the brain. Inset: Magnified image of boxed region. (B) Legend of 31 different cell populations mapped in A. (C) The same data represented as a UMAP plot. (D) The same tissue was also probed for genes of interest. A subset is shown, but 123 other genes were also probed. For each probe, one can detect in what brain region and in what cell each gene is expressed. Note the different expression patterns. Figure courtesy of Dori Schafer, PhD, UMMS.

Baer connected with Vizgen, the Boston biotech company pioneering the next generation of genomics, expanding the impact of spatial context, and demonstrating the possibilities of in situ single-cell spatial genomics.  Vizgen is commercializing the MERSCOPE™ Platform, the only integrated solution for MERFISH, and the first complete platform for single-cell spatial genomics. For Baer, “It’s really been critical for us to partner with a team that is fully committed to implementing MERFISH at UMMS”.

As an early adopter of Vizgen’s platform, SCOPE is already offering services that demonstrate the power of MERFISH. The lab had struggled with single-cell RNA-seq and Slide-seq, but the pivot to MERFISH was painless. Baer explained, “The sensitivity of MERFISH allowed them to map things that they didn’t think were going to be possible. We are just at the tip of the iceberg with these data.”

Vizgen recently launched a Data Release Program, starting with its MERFISH Mouse Brain Receptor Map, the first freely available spatial genomics dataset. Generated with the MERSCOPE™ platform, this dataset contains the MERFISH measurement of a gene panel containing 483 total genes including canonical brain cell type markers, GPCRs, and RTKs within the mouse brain, totaling half a billion transcripts from nearly half a million cells. The goal of the Vizgen data release program is to provide a valuable resource to the research community to explore the possibilities of spatial context, while demonstrating the power of MERSCOPE™. Vizgen is currently offering a limited summer release program with full launch later this year.

 

To learn more about MERSCOPE™, visit www.vizgen.com/products