INVESTIGATION OF SUBPOPULATION HETEROGENEITY AND PLASMID STABILITY IN RECOMBINANT ESCHERICHIA-COLI VIA A SIMPLE SEGREGATED MODEL

Many microbial and cell cultures exhibit phenomena that can best be described using a segregated modeling approach. Heterogeneities are more marked in recombinant cell cultures because subpopulations, which often exhibit different growth and productivity characteristics, are more easily identified by selective markers. A simple segregated mathematical model that simulates the growth of recombinant Escherichia coli cells is developed. Subpopulations of different growth rate, plasmid replication rate, and plasmid segregation probability are explicitly considered. Results indicate that a third mechanism of plasmid instability, referred to here as a ''downward selective pressure,'' is significant when describing plasmid loss in batch and chemostat cultures. Also, the model agrees well with experimental data from cultures under antibiotic selective pressure. Finally, model simulations of chemostat cultures reveal the importance of initial conditions on culture stability and the possible presence of nonrandom partitioning functions.