The history of spatial transcriptomics at Sanger

By Shannon Gunn, Senior Science Writer, Wellcome Sanger Institute

Discover how the Wellcome Sanger Institute has been at the forefront of spatial research, exploring how trillions of cells organise, communicate and work together to form a human being. For more than 15 years, Sanger scientists have pushed the boundaries of modern genomics, helping to map the human body in greater detail – cell by cell.

enetics has massively evolved from Gregor Mendel’s 19th-century discovery of inheritance. The structure of DNA was revealed in 1953, enabling molecular biology and genetic engineering. Then, the Human Genome Project in the late 20th century ushered in large-scale genomics, while next-generation sequencing made genome and transcriptome analyses routine. In the 2010s, single-cell sequencing exposed cellular diversity, and spatial transcriptomics now maps gene activity within tissues, bringing unprecedented insight into biology.

Spatial transcriptomics is becoming a vital part of our work here at the Wellcome Sanger Institute, so here we look back at the early adoption of these technologies at Sanger and the components that enabled them to become a part of our core operations.

Advancements in spatial technologies

Our spatial journey started back in the 2010s with the beginning of our efforts on single-cell biology, which involves the study of genes, molecules and activities in each individual cell. This is in contrast to so-called ‘bulk’ approaches where many cells are analysed together. Single-cell analysis helps scientists see differences between cells, understand how they work and find rare cell types. This work was sparked at the time by former Head of the Cellular Genomics programme and Co-Founder of the Human Cell Atlas, Professor Sarah Teichmann, former Associate Faculty, Dr John Marioni, former Group Leader, Dr Thierry Voet and former Head of Research and Development, Dr Harold Swerdlow – leading to the formation of the Sanger-EBI Single-Cell Initiative. This Initiative was set up to develop and apply methods to gain information on the complete genetic contents of single cells in a high-throughput manner.

This work was driven by the availability of single-cell transcriptomic technologies, most importantly the 10x Genomics Chromium platform. This is a droplet-based technology that captures each cell in a tiny droplet with special barcodes to help track which genes are expressed by which cells. This can make it easier to understand how different cells in a tissue work and interact.

Whilst single-cell assays can capture very detailed information about each cell, it was apparent at the time that cells were being taken from their native environment and studied without spatial tissue context. In solid organs where cells are located, the identity of their neighbours, their tissue niche, their microenvironment, their communication – all of these are key determinants of a cell’s identity and behaviour. The team and wider single-cell community recognised that spatial resolution was needed to deepen our insights.

At this time, spatial technologies were at very early stages, so the Institute decided to bring in leading researchers to help drive this process. In 2018, Dr Omer Bayraktar joined the Cellular Genomics programme as a Group Leader. Omer had the desire to do spatial transcriptomics to understand cells in their native tissues in the human body with a focus on the brain. During this time, the Human Cell Atlas (HCA) was also kicking off – a project which aims to map all the cells of the human body to understand more about health and disease. This project – co-founded by Sarah Teichmann and strongly driven by research at the Institute – was generating a lot of single-cell data, but the community wanted to start doing spatial too. In response, the High-Throughput Spatial Genomics group was formed at the Institute in 2019 to develop and scale spatial transcriptomics. Their work enables the integration of spatial data with single-cell atlases, helping build detailed, 3D maps of human tissues relevant to health and disease.

In the same year, Dr Kenny Roberts, now Senior Staff Scientist, joined Omer’s team as a postdoc and worked on a project to help set up spatial. They started by doing RNAscope – a commercially available platform that uses single-molecular fluorescence in situ hybridisation (smFISH) to visualise and quantify individual RNA transcripts within cells and tissues using fluorescent probes. They were using this to assay a small number of genes – approximately four to 12 – and generated data that contributed to various early HCA papers.

Read more at… Wellcome Sanger Institute