Cell Engineering to Increase Productivity

An important tenet for achieving highly productive processes is the achievement within the bioreactor of a high viable cell concentration and its subsequent maintenance for an extended period. The latter requires the death rate to be minimized. This section describes cell engineering approaches evaluated with GS cell lines to minimize the death rate. 

Al-Rubeai et al. [39] showed that the major cause of cell death in animal cell culture is through the induction of apoptosis (programmed cell death) pathways by chronic, rather than acute, insults. As 

Since apoptosis can be induced by nutrient deprivation, one approach to limit its extent is to prevent nutrient hmitation. 

The use of fed-batch operations can delay the onset of apoptosis in GS-NSO cell hnes and substantially reduce its extent [3, 41], thereby increasing the IVG. However, the use of a fed-batch process does not completely eliminate apoptosis. Another approach to increasing process productivity is to engineer resistance to apoptosis into the cell lines. 

As activation of the apoptotic pathways results in destruction of the cell, the pathways must be tightly regulated. The best understood regulatory mechanism involves the Bcl-2 family of proteins. Some members of the Bcl-2 family stimulate apoptosis (e.g., Bax, Bak and Bid), whilst others have an anti-apoptotic function (e.g., Bcl-2 and Bc1-xl). Bcl-2 family members have been postulated to inhibit apoptosis by a number of mechanisms [42, 43]. 

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