Chapter 3
Gas feed
Liquid feed
Acid E(ase
Exhaust gas
— Effluent liquid
Substrate reservoirs
Figure 3.1 A continuous, stirred tank bioreactor with feed of a liquid medium from a substrate reservoir
and a feed of gaseous medium through a sparger. pH is typically kept constant by adding acid or base
from separate reservoirs. *
Note 3.1 Time dependent output with constant input variables.
Sometimes a time independent set of input variables does not lead to time independent output variables.
Some microbial cultures seem unable to reach steady state in a certain range of (time independent)
operating conditions. All outputs oscillate with an oscillation time that depends on the input
variables. This is further discussed in Chapter 8 and 9.
The cells may suddenly, and for no apparent reason change their behavior. A product - it could be
penicillin - is suddenly not being produced at the same constant rate, which has been measured for
many hours of the apparently steady state operation. After a relatively short period the cells may
totally have lost their ability to produce a particular metabolic product. In other cases the cells may
become “sick” and die. A cell count of viable cells will show a gradually diminishing fraction of
viable cells, i.e. cells that are able to grow. All these cases are typically a consequence of occurrence
of natural mutations, which may be followed by selection of the mutated cells in the bioreactor.
When we use the presumably steady state, continuous reactor to measure what should be steady state
rates of production of biomass and metabolic products it is, of course a surprise not to have time
independent outputs. Still, the unexpected results might offer opportunities for challenging research, or
the observation of the phenomena in well-controlled laboratory reactors may prevent later disasters when
the laboratory results are to be used in an industrial scale process. Thus the observation of oscillating
reactions indicates that the kinetics of the overall reaction is of a kind, which does not admit to a steady
state output, even when the input is constant - a situation also encountered in chemical reaction
engineering. The gradual cessation of synthesis of a desired product indicates that the environment has
changed in a subtle fashion which it will take much experimental effort to explore - a slight difference in
medium sterilization or in inoculation of the reactor, a different batch of yeast extract used as nitrogen
source in the feed medium. Events observed in the steady state laboratory culture could also have their
origin in the genome of the cell - a slight change in the expression of certain genes could lead to a
cascade of events observed on the macroscopic level in the reactor.
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