Abstract
Static and dynamic characteristics of continuous cultures of recombinant methylotrophs, which are designed to improve the selectivity of plasmid-bearing cells and the plasmid stability, are investigated in detail. Operational regions in which coexistence (survival of plasmid-bearing and plasmid-free cells) operation is feasible have been identified in the entire space of kinetic parameters and operating variables. The stability characteristics of each steady state are examined. The existence of oscillatory states around the coexistence steady state is investigated using the dynamic (Hopf) bifurcation analysis. For proper startup of the continuous culture operation, it is critical to identify the sets of initial conditions, if any, which lead to transients that ultimately result in washout of plasmid-bearing cells and avoid such conditions. For the numerical illustrations presented, the coexistence steady state happens to be locally stable over much of its region of existence, particular for the operating conditions corresponding to maximum productivity.
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