As with real estate, location matters greatly for cells. Douglas Strand confirmed that truth last year when he used a new technique to map gene activity in bladder cancers. Until recently, scientists wanting to know all the genes at work in a tissue could analyze single cells without knowing their position, or they could measure average activity levels of genes across thousands of cells. Now, an emerging technology called spatial transcriptomics combines precision and breadth, mapping the work of thousands of genes in individual cells at pinpoint locations in tissue. That, Strand says, has been a “total game changer” for his research.
The virtual Advances in Genome Biology and Technology (AGBT) meeting this month was a big coming-out party for the technique, which is revealing whole new landscapes of gene expression. Strand, for example, reported finding that cells surrounding bladder tumors, though outwardly normal, display many of the same gene activity changes as the cancer. “They looked more like tumor than normal tissue,” says Strand, who works at the University of Texas Southwestern Medical Center. He found surprises within the tumors, too: hidden patterns of gene activity suggesting some of the cells are more likely than others to spread beyond the bladder.
Other biologists at the meeting reported using the technique to study Alzheimer’s disease, track the dynamics of different types of T cells, and study lung, heart, and other tissues in COVID-19 patients. “The field is developing very, very fast,” says Aparna Bhaduri of the University of California, Los Angeles, who uses it to examine developing human brains.
Scientists studying cells have long been able to examine the activity of a few, select genes in intact tissue—for example, by engineering a gene to tack on a fluorescent tag to the protein it encodes. By 2010, traditional transcriptomics, which examines cellular activity of many, if not all, known genes by probing for the messenger RNA (mRNA) transcripts they encode, took off. But those studies require tissues to be ground up first, so the data represent the average activity of genes in millions of cells.
More recently, biologists have begun to monitor all the genes of single cells, uncovering vast differences in gene activity between different cell types and variation even within types. But because those cells are extracted from tissue with enzymes or teased out with lasers, microscopic tweezers, or other methods, the influence of their precise location and neighbor cells is lost. “We could see the individual parts, but we didn’t know how the parts fit together,” explains Joseph Beechem, a biophysicist at NanoString Technologies, a leading company for spatial transcriptomics and related methods.
Then in 2016, Swedish researchers described in Science how they managed to keep track of cells’ locations while assessing the activity of about 200 of their genes. The group put thin slices of a tissue onto slides precoated with short, known sequences of DNA, meant to act like identifiable barcodes, attached to other DNA designed to latch nonspecifically onto any mRNA nearby. The team treated the tissue with detergent to make cells leak their mRNA, which linked to the anchored, barcoded DNA, marking which cell the mRNA came from. Then, they added enzymes and DNA bases to the slice to translate each mRNA into a complementary DNA strand. Sequencing that strand along with its position-identifying barcode revealed the active parent gene and its position. Those data enabled computer programs to reconstruct the tissue locations of all the active genes.
Multiple companies have begun to sell expensive machines that conduct such spatial transcriptomics analyses, making it possible to study thousands of genes in hundreds of cells in their proper places. That “can tell you a lot about how cell communication might break down in disease,” says Aviv Regev, a computation and systems biologist who heads the Genentech Research and Early Development unit of Roche.