Sense and nonsense from a systems biology approach to microbial recombinant protein production

The 'Holy Grail' of recombinant protein production remains the availability of generic protocols and hosts for the production of even the most difficult target products. The present review provides first an explanation why the shock imposed on bacteria using a standard induction protocol not only arrests growth, but also decreases the number of colony-forming units by several orders of magnitude. Particular emphasis is placed on findings of numerous genome-wide transcriptomic studies that highlight cellular stress, in which the general stress, heat-shock and stringent responses are the underlying basis for the manifestation of the deterioration of cell physiology. We then review common approaches used to solve bottlenecks in protein folding and post-translational modification that result in recombinant protein deposition in cytoplasmic inclusion bodies. Finally, we suggest a generic approach to process design that minimizes stress on the production host and a strategy for isolating improved hosts.