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Interrogating the spatial organization of tissue and cells with multiomics is changing biology. “We’re basically going to rewrite the textbooks of almost every piece of the life sciences with this technology,” says Joseph Beechem, PhD, chief scientific officer at NanoString in Seattle. At the 2022 AGBT (Advances in Genome Biology and Technology) meeting in Orlando, NanoString announced new platforms and tools that will accelerate this transformation.

In 2019, NanoString unveiled its first spatial biology instrument, the GeoMx® Digital Spatial Profiler platform. Today, this platform provides analysis of the whole transcriptome and 100+ proteins with spatial resolution of about 50–100 microns. Beechem calls the GeoMx “the first fully integrated platform—not some kit or consumable —that was an instrument to examine key substructures in tissue at unlimited plex,” which is functional spatial biology.

At AGBT, NanoString announced the CosMx™ Spatial Molecular Imager, which provides single-cell and subcellular analyses, with resolutions down to <100 nanometers. This system analyzes up to 1,000 mRNA transcripts and 100 proteins across an extremely large viewing area of 300 square millimeters. The CosMx is launched with 1,000-plex transcript panels for human immuno-oncology and mouse neurobiology as well as denovo custom 300-plex.

Taking analysis into the cloud

The large amounts of information from spatial biology create challenges in handling and analyzing data. In Orlando, NanoString introduced its AtoMx™ Spatial Informatics Portal, a cloud-based, informatics ecosystem for spatial biology that includes advanced analytics and allows simple data sharing for collaboration around the world. “Life science is now ‘big science,’” Beechem says. Consequently, AtoMx allows research teams to collaborate, independent of physical location, to produce and analyze gigantic datasets as easily as sharing an Excel file.

The specific analysis and collaboration mode(s), however, vary between various projects. “We designed the software to be as flexible as possible,” Beechem explains. For example, NanoString scientists wrote the suite of analytical tools in an open way that allows scientists to “mix-and-match” NanoString tools with any open-source tools developed anywhere in the world. Beechem notes that at the center of AtoMx there is “a completely configurable pipeline orchestrator, allowing custom processing of millions-of-single-cells as easily as making a flowchart of the operations desired.”  In addition, both GeoMx and CosMx data are stored in AtoMx in a completely flexible Data Lakehouse structure, ready to be examined using artificial intelligence and machine learning approaches.

AtoMx works with data from both GeoMx and CosMx. “So, our platform from 2019 gets a whole new capability associated with that,” Beechem says.

Extensive applications

Although NanoString started with immuno-oncology and neurobiology panels, spatial biology applies to all organisms across all their development. As an example, Beechem describes applying GeoMx to a developing mouse embryo. “We did whole transcriptional profiling of the embryo over time to study organogenesis,” he says.  “With this study, we were able to solve the “lost in space” problem, where clusters of cells observed in UMAP plots from single-cell RNA sequencing of mouse organogenesis can now be given their true spatial home. (An example presented at AGBT was a cluster of cells mapped directly to the wall of a developing mouse heart left ventricle.)  “We’re moving from visual developmental biology to molecular developmental biology.”

The applications also cover all scales. “GeoMx explores how tissues and substructures function (aka “public life”), using whole transcriptome examination of the islet of Langerhans,” Beechem explains. “Then, CosMx emphasizes how individual cells of the islet self-assemble and organize and talk to each other (aka their “private life”), fine-tuning all aspects of their public-life function (secretion of insulin and glucagon).”

In a lymph node, for example, Beechem used both GeoMx and CosMx to explore the pathways and communication between immune cells. “We did GeoMx whole transcriptome profiling of unique spatial domains, especially the germinal center of a lymph node, and we discovered a brand-new spatial compartment,” he says.  “Then, using CosMx 1000-plex on the same lymph node, we were able to show exactly which “private-life” set of cell conversations and receptor-ligand interactions in the germinal center had been generating the new functional biology that we discovered with GeoMx whole transcriptome.”

The spatial biology platforms from NanoString will reveal novel discoveries in many organs. One of those is the brain. In a developing mouse brain, NanoString scientists tracked factors secreted by astrocytes and microglia. “Then observe microglia actively digesting away some synapses and forming them in other areas,” Beechem says.  Key to making these very detailed “private life” measurements is CosMx’s best-in-class 1000-plex capability, allowing cell typing, receptor-ligand interactions, and cell state/activation to be simultaneously measured.

Gaining such insights from spatial biology depends on integrated technology. In thinking of NanoString’s platforms, Beechem says, “Between GeoMx and CosMx, you basically cover all the dominant spatial scales that exist in spatial biology, and then AtoMx gives you this very simple way that people can interact with this big data with the rest of the world to find true insights into spatial biology.” He adds, “Now, every individual scientific investigator can become a big data center and create their own personalized cell atlases, accomplishing scientific discovery in a way that is truly enabling.”

 

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