The structure and organization of cells within organs is essential to their function, but nowhere in the body is this more spectacular than the brain. There, sprawling, snowflake-like neurons have grown into a precise arrangement, reaching out to neighboring cells to form neural circuits. Communication within neural circuits, made possible by spatial positioning, forms the basis of our physiology. Recently, a high-resolution cell atlas generated by MERFISH (multiplex error-robust fluorescence in situ hybridization) technology has mapped this spectacular organ with unmatched resolution, depth, and scale. The atlas catalogs cells as they exist in the intact biological system and will allow us to learn more about rare cell types and sparsely expressed cell signaling receptors fundamental to health and disease.

The brain, a lung, a tumor: each contains a complex array of cell types arranged in an intricate spatial pattern that is critical to their role within the tissue. While work is underway to create an atlas of cellular diversity across tissues, traditional methods either have sufficiently high multiplexing capacity but lack spatial context, or they provide spatial information but lack the multiplexing capacity to identify subtle variations in cell type or state. This limitation precludes a comprehensive view across a whole tissue, including rare cells, as they exist within a tissue of interest. Since understanding how the molecular and cellular organization of a biological tissue contributes to its functionality is fundamental to developing treatments that target the cell biology underlying diseased states, improved tools that map biological systems with both high spatial resolution and high multiplexing capacity promise to deliver new, clinically relevant insights into the functional composition of biological systems. The recently developed multiplexed error-robust fluorescence in situ hybridization (MERFISH) method provides information about gene expression at subcellular resolution and reveals cell type, state, and cell-cell interaction by quantifying the expression and exact location of hundreds to thousands of transcripts within intact tissues. MERFISH represents a major advancement toward directly interrogating rich cellular heterogeneity and is being applied to gain insight into the biological complexity within and around us.