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sonable agreement between the toggle theory and experiment suggests
that the theoretical design of complex and practical gene networks is a
realistic and achievab le goal. Furthermore, the genetic toggle switch
forms the basis for a forward engineering approach to the study of gene
expression. Such an approach may be more effective than the reverse
engineering approach more typically used in cellular biology, because it
permits the complete manipulation of all elements in the system . The
enormous complexities of natural gene networks can be engineered out
of the toggle switch and future experimental devices. Thus, synthetic
gene networks, which serve as highly simplified, highly controlled mod–
els of natural gene networks, can be used to test and refine a more gen–
eral, quantitative theory of gene regulation.
As a practical device, the genetic toggle has significant implications for
gene therapy and biotechnology. Because the toggle theory is qualitative,
and thus general, the fundamental design is applicable to any organism,
including human cells. Recent work demonstrated the controllable
expression of a recombinant EPQ gene in mice. The drawback of this
system is that it requires the sustained ingestion of tetracycline. Long–
term ingestion of tetracycline may be inconvenient or impractical for
medical reasons. A better method for the expression of EPQ or any other
transgene is to place it under the control of a toggle switch. Expression
of the gene will then remain in either the "on" or "off" state until the
toggle is switched by the transient ingestion of an appropriate drug.
The toggle also represents the core technology for additional genetic
control devices. Minor modifications to the toggle produce a genetic
sensor-a monostable, inducible gene expression system with a nearly
ideal and adjustable induction threshold. Furthermore, the hysteresis
inherent in such an inducible network suggests a straightforward way to
construct a genetic oscillator-a network that alternately expresses two
proteins. In addition, the toggle switch itself is an artificial cellular
memory unit that could provide cells with programmable, temporal
decision-making capability. Finally, the multistability demonstrated by
the toggle switch suggests a way to achieve robust sequential expression
of a gene-by hopping from state to state.
Simple networks such as the genetic flip-flop demonstrate the feasi–
bility of building synthetic genetic circuits with basic computational
functions such as memory and timing, but their practical applicability is
somewhat limited. Just as the impressive capabilities of electronic cir–
cuits arise from the integration of hundreds to millions of individual ele–
ments, the utility of biological circuits will likely be apparent only when
many functional elements are brought together. Such an integrated bio-
