Figure 2.

Stochastic fluctuations in mRNA and protein level manifest as phenotypic interconversion at the single-cell level, which generates heterogeneity and a tendency to restore homeostatic heterogeneity at the population level. (a) and (b) Local interconversion exploring a graded phenotypic distribution. (c) Rate coefficients for a minimal Markov model with simplified drug-sensitive and drug-resistant compartments. Drug-sensitive cells replicate with rate coefficient r_S, are cleared with rate coefficient m_S, and convert to the drug-resistant phenotypic state with rate coefficient c_S. Analogous rate coefficients describe the dynamics of the drug-resistant cells. (d) Microscopic description of the minimal model in (c) and equations (1) and (2): Individual cells adopt future phenotypes according to the outcomes of spins of wheels of fortune. The configurations of the roulettes depend on the cells’ immediate phenotypes, rather than their historical states. (e) Gradual approach toward steady-state mixture of drug-sensitive and drug-resistant cells from an initial population of 20 drug-sensitive cells (r_S = r_R = m_S = m_R = 0 and c_S = c_R = 1). (f) Gradual approach toward steady-state heterogeneous population composition from an initial population of 15 drug-resistant cells. (g) Approach toward both steady-state population composition and net expansion rate starting from a purely drug-resistant population (r_S − m_S = 1, r_R = m_R = 0, and c_S = c_R = 1).