image: Mutations can now be created and examined (in red) among otherwise healthy cells (multi-coloured), revealed by a new functional genomics technology, called Spatial Perturb-Seq, developed at A*STAR Genome Institute of Singapore (A*STAR GIS).
Credit: A*STAR Genome Institute of Singapore (A*STAR GIS)
SINGAPORE - Researchers from A*STAR Genome Institute of Singapore (A*STAR GIS) have developed a new technology that allows scientists to study how genes function within intact living tissue. Unlike conventional methods that require tissues to be broken down into individual cells, which removes important information about how cells interact with and influence one another, the new approach preserves the spatial relationships between cells. This allows researchers to see how genetic changes affect both the individual cells and their neighbours. The findings were published in Nature Communications.
The new technology, Spatial Perturb-Seq, enables researchers to change selected genes and observe cells in their native tissue environment. The scientists used CRISPR-Cas9, a gene editing tool, to modify multiple genes in brain cells. Each edited cell was assigned a unique barcode, allowing the researchers to identify and track which genetic change had been made in each cell. Importantly, the tissue remained intact, allowing researchers to see exactly where each cell was situated, who its cellular neighbours were, and how the impact from each mutation rippled through the tissue environment.
The team applied the technology to 18 genes linked to neurodegenerative diseases such as Parkinson's, Alzheimer's, and amyotrophic lateral sclerosis (ALS). They observed not only how the edited cells responded, but also how unedited, otherwise healthy, neighbours were affected. This is crucial because many diseases are shaped not only by what happens inside sick cells, but also by how those cells impact surrounding tissue. Neurons in brains communicate with each other in networks important for brain function, so genetic changes in one cell can affect many others. Here, Spatial Perturb-Seq uncovered new biological findings in genes that affect cell to cell signalling in the brain. The same principle applies beyond neurodegeneration. In cancer, for example, tumour cells don't just grow independently; they impact and alter the behaviour of surrounding healthy cells.
By revealing how disease-linked genes behave within intact tissue, this technology could help researchers better understand disease mechanisms and identify more precise therapeutic targets.
Dr Kimberle Shen Yanyin, Senior Scientist at A*STAR GIS and first author of the paper, said, “We built Spatial Perturb-Seq as a powerful technology that is easily used, so that we can now literally see each gene mutation and its consequences in the tissues and organs. This enables new target discovery and mechanistic study important for new drugs.”
Dr Chew Wei Leong, Senior Principal Scientist, Laboratory of Synthetic Biology & Genome Editing Therapeutics, A*STAR GIS and lead author, said, “For the first time, we are not just reading genes – we are revealing the full picture of where and what they do within the organs. This shows us precisely what disease mutations to target – that's the answer that matters for patients."
The researchers at A*STAR GIS are currently applying this technology to tumour models to determine how cancer cells interact with healthy tissues.
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About A*STAR Genome Institute of Singapore (A*STAR GIS)
The A*STAR Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to achieve extraordinary improvements in human health and public prosperity. Established in 2000 as a centre for genomic discovery, A*STAR GIS pursues the integration of technology, genetics, and biology towards academic, economic and societal impact, with a mission to harness genomic technologies for a better Singapore and world.
Key research areas at the GIS include RNA & DNA Technologies, Single Cell & Spatial Technologies), Precision Medicine, Population Genomics, and AI & Compute. The genomics infrastructure at the GIS is also utilised to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.
For more information about GIS, please visit www.a-star.edu.sg/gis.
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About the Agency for Science, Technology and Research (A*STAR)
The Agency for Science, Technology and Research (A*STAR) is Singapore's lead public sector R&D agency. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit the economy and society. As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by improving societal outcomes in healthcare, urban living, and sustainability. A*STAR plays a key role in nurturing scientific talent and leaders for the wider research community and industry. A*STAR’s R&D activities span biomedical sciences to physical sciences and engineering, with research entities primarily located in Biopolis and Fusionopolis. For ongoing news, visit www.a-star.edu.sg
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Journal
Nature Communications