Systems biology in 3D space – enter the morphome

•We define the morphome as the distribution of matter in a 3D object.•Morphomics methods characterize or quantify 3D data at ground truth level.•Stereology is the most efficient and precise archetypal morphomics method.•Stereology can be applied to solve the big data problem in serial EM.•Stereology can be applied to make quantitative links between nanoscale imaging modes.

Systems-based understanding of living organisms depends on acquiring huge datasets from arrays of genes, transcripts, proteins, and lipids. These data, referred to as ‘omes’, are assembled using ‘omics’ methodologies. Currently a comprehensive, quantitative view of cellular and organellar systems in 3D space at nanoscale/molecular resolution is missing. We introduce here the term ‘morphome’ for the distribution of living matter within a 3D biological system, and ‘morphomics’ for methods of collecting 3D data systematically and quantitatively. A sampling-based approach termed stereology currently provides rapid, precise, and minimally biased morphomics. We propose that stereology solves the ‘big data’ problem posed by emerging wide-scale electron microscopy (EM) and can establish quantitative links between the newer nanoimaging platforms such as electron tomography, cryo-EM, and correlative microscopy.