The crowded field of spatial transcriptomics has a new contender. BGI-Research’s Stereo-Seq (SpaTial Enhanced REsolution Omics sequencing) technology has entered the ring with the publication of four separate papers in Cell Press on the same day. These first panoramic spatial atlases of life examine the cellular dynamics of organisms at different developmental stages and provide potentially significant new information for disease treatment, development and aging, and an improved understanding of biological evolution.
The Stereo-Seq technique is published in Cell, in the paper, “Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays.” The other three studies, published in Developmental Cell, describe using Stereo-Seq to map developing Drosophila embryos and larvae, zebrafish embryogenesis, and transcriptome profiling in Arabidopsis leaves.
China’s BGI-Research is one of the three arms of BGI Group, along with MGI and BGI Genomics. Ao Chen, PhD, chief scientist of spatiotemporal omics and director of biochemistry institute at BGI-Research, joined BGI-Research in 2013. Chen spent his first years at the company as part of the team that developed the DNA nanoball technology (DNB-seq) which is used in MGI’s sequencers. Part of the progress they made was maximizing the density of the nanoballs and developing the largest sequencing chip.
These tools are now being applied to RNA. Chen’s team transformed the sequencing chip to the Stereo-chip which can capture RNA. DNBs carry the information, location, and spatial barcode so that each RNA can be labeled individually via the DNB.
Stereo-Seq, Chen told GEN, has two major benefits. The first is that they can have subcellular resolution of 500 nanometers which, he says, is the highest resolution so far. The other advantage is the large (centimeter level) field of view.
The process starts with the barcoded DNBs. Before loading, the sequence of the barcode and location of the DNB is not known. After loading, 25 cycles of sequencing reveal every DNB’s location and barcodes. Then, poly-T is added to the DNB so that the chip is ready to capture the RNA. The slides and reagents are packaged and sent as a Stereo-Seq kit to collaborators. After researchers perform cryo-sectioning on the slides, they are sent back to BGI. Here, the tissue is permeabilized and reverse transcription is performed. The labeled cDNA is rinsed off and the spatial barcodes are mapped.
In addition to distributing kits, BGI is building Stereo-labs around the world—in the United States, Europe, Australia, Singapore, and China. The Stereo-lab in the United States is located in San Jose, CA—the U.S. branch of BGI-research. Researchers can also arrange to have a Stereo-lab built in-house if they want to establish the pipeline in their own center.
Collaborators used Stereo-Seq to examine the early embryonic development of the mouse, in particular from 9.5 to 16.5 days during which embryonic development is occurring at the fastest rate. The data generated the Mouse Organogenesis Spatiotemporal Transcriptomic Atlas (MOSTA), which maps with single-cell resolution and high sensitivity, the kinetics and directionality of transcriptional variation during mouse organogenesis.
For the first time, scientists were able to produce a series of high-precision maps showing the precise location of the roughly 300,000 cells from the day 16.5 embryo. BGI-Research used this information to produce a panoramic atlas of the mouse and gain insight into the molecular basis of cell variation and differentiation in developing tissues of the brain, including the dorsal midbrain.
“The development of a single-cell analytical approach over the past twenty years has really made a remarkable difference in our ability to understand how cells differ from each other. More recently, it started to be possible to combine that analysis with where cells are in a tissue or organoid tissue section,” said Patrick Maxwell, FMedSci, professor of physic and head of the School of Clinical Medicine at the University of Cambridge. “In my view, this new paper takes this to a new level by combining a substantial size field of view, making it possible to analyze a tissue on a scale of a developing mouse embryo, together with a very high resolution with a very deep transcriptomic read depth.”
The BGI-led team carried out similar embryonic research with the zebrafish which has a gestation period of only 24 hours, and also produced a 3D model of the cellular map of Drosophila. The spatiotemporal transcriptomic atlas of embryonic development in Drosophila, zebrafish, and mouse has opened new doors for the study of embryonic patterning and related molecular mechanisms during embryonic development, providing important data references for further work as well as a benchmark for unraveling embryonic evolution.
By applying Stereo-Seq research on the leaf cells of the Arabidopsis plant, the researchers were able to overcome the long-term difficulty for researchers to conduct spatially-resolved single-cell omics studies on leaves and other plant tissues. BGI Research was able to demonstrate that Stereo-Seq technology can be applied in plant science research and crop breeding research. Some key applications include understanding key genes involved in seed development, mechanisms behind drought resistance, mechanisms behind heat resistance, and mechanisms behind salt tolerance, for staple crops from rice to wheat to maize. This can contribute to the cultivation of high-quality, stress-resistant crop strains important for many global sustainability initiatives.
Concurrently with the papers’ publication, the SpatioTemporal Omics Consortium (STOC)—a group that includes an international group of roughly 80 scientists—was announced.
“There are many great cell atlas scientists that come from different fields,” noted Longqi Liu, PhD, chief scientist of single-cell omics and director of cell science institute at BGI-Research. They had the idea to form a group like this at BGI a few years ago, Liu noted, but it was the suggestion of a Cell editor that got the consortium off the ground.
The BGI-research team wants to use the Stereo-Seq technology to create more maps. Indeed, they posted a preprint in March of this year describing a comprehensive single-cell spatial transcriptome map of monkey brains. They used this technology to analyze 130 slides in about one week’s time, Chen told GEN.
The larger goal of the STOC is to bring together spatial researchers to “unite, organize, advance, and share global scientific efforts to map the spatiotemporal multi-omic atlases of organisms and to develop the analytical tools with which to gain novel biological insights across physiology, development & aging, disease, and evolution.”