Massively parallel evolution reveals a biophysical scaling law between cell size and internal cell density

Using a massively parallel evolution platform, we selected Saccharomyces cerevisiae for increased cell size to test how cellular architecture adapts to biophysical constraints. As cells evolved larger size, they became less spherical and showed reduced carrying capacity without changes in maximum growth rate. Optical diffraction tomography revealed that individual cells with greater volume consistently exhibited lower internal density, a relationship that persisted across replicate populations and evolved isolates. The largest cells often contained enlarged vacuoles, suggesting that vacuole expansion may sometimes contribute to reduced density. Extending this analysis beyond yeast, 68 species spanning major phylogenetic clades also demonstrate a negative scaling between cell density and cell size. Together, these results suggest that decreased internal density is a conserved consequence of increasing cell size, revealing a fundamental cellular trade-off between volume expansion and material concentration.