Systems Biology (Methods in Molecular Biology)

The resultant “mutated” or “synthetic” bacteria culture repro-

duced the predicted oscillatory dynamics of the model (Fig.9b).

This work provided the first known documented evidence that

a simple ordinary differential equations based model could be used

to design artificially fused cells, whose function can be controlled in

silico prior to actual experimentations. Thus, complex behavior of

livings cells may be guided by simple rules. However, it is important

to note that livings cells are not homogenous in their behavior, or

identical in their molecular constituents. The effect of heterogene-

ity gives rise to variability in cell to cell behavior (seeSubheading6).

3.5 Bistable
Response

Biological switches play an essential part in a living system’s func-

tionality. There are times when certain genes are turned on or off

periodically to develop a functional response for survivability or

adaptability. For example, the survival pathways of immune cells

are initially activated to fight invading pathogens, and are, subse-

quently, cleared through the switching to the apoptotic pathway to

prevent chronic inflammation [4].

Collins and colleagues [33] constructed a simple genetic toggle

switch in E. coli to function as a controllable memory unit

(Fig.10a), with the aid of a simple differential equation model,

similar to the Goodwin model with Hill coefficient:

du

dt

¼

α 1

1 þvβ

u ð 26 Þ

dv

dt

¼

α 2

1 þuγ

v ð 27 Þ

whereuandvrepresent the concentration, andα 1 andα 2 are

effective synthesis rates, of repressors 1 and 2, respectively.βandγ

are the cooperativity of repression of promotors 1 and 2, respec-

tively (Fig.10a).

In this system, two stable states are possible when inducers

1 and 2 are absent, (1) a “low” state where repressor 2 is transcribed

when repressor 1 is repressed and, (2) a “high” state where repres-

sor 1 is transcribed when repressor 2 is repressed (Fig.10b).

In a stable position, controlling inducer concentration for the

repressed repressor causes total transcription till the active repressor

is repressed. Thus, control of inducers in the theoretical model

allows switching between two stable states.

Using the knowledge obtained from their simple model, Col-

lins and colleagues subsequently constructed two classes of toggle

switch plasmids, pTAK class (thermal inducer) and pIKE class

(chemical inducer), inE. coliand demonstrated bistability in the

expression of the tagged green fluorescent protein or GFP (see

Fig. 4 of ref.33).

188 Kumar Selvarajoo