For the fourth entry in the series, I will not introduce one, but two papers, published back to back in a January 2000 issue of Nature. The particularity of these articles is not that the described models presented novel features or revealed new biological insights. However, they can be considered as marking the birth of Synthetic Biology as a defined subfield of bioengineering and an applied face of Systems Biology. It is quite revealing that they focused on systems exhibiting the favourite behaviours of computational systems biologists: oscillation and multistability.
Both papers were published back to back in a Nature issue of January 2000.
Elowitz MB, Leibler S (2000) A synthetic oscillatory network of transcriptional regulators. Nature, 403:335-338. http://identifiers.org/pubmed/10659856
This paper presents a model, called the repressilator, formed by three repressors in tandem. Each of them is constitutively expressed, this expression being repressed by one of the others. Deterministic and stochastic simulations show that for high transcription rate and sufficiently high protein turnover, the system oscillates, the three repressors being expressed in sequence.
The authors implemented the model in bacteria, using the Lactose repressor of E Coli (LacI), a repressor from a tetracycline-resistant transposon (TetR) and a lambda phase repressor (CI).
They indeed observed an oscillation, detected by a reporter plasmid under the control of a TetR sensitive promoter. Interestingly, the period of the oscillation is longer than the duplication time and a full oscillation spans several generations of bacteria. You can download a curated version of the repressilator in different formats from BioModels Database (BIOMD0000000012).
Gardner TS, Cantor CR, Collins JS (2000) Construction of a genetic toggle switch in Escherichia coli. Nature, 403: 339-342. http://identifiers.org/pubmed/10659857
The second paper builds on a bistable switch, formed by two mutual repressors (constitutively expressed in the absence of the other). If the strength of the promoters is balanced, the system naturally forms a bi-stable switch, where only one of the repressor is expressed at a given time (stochastic simulations can display switches between the two stable states).
The authors built two versions of this switch, in a way that allowed to use external signals to disable one of the repressions, therefore stabilising specifically one state. Interestingly, the authors built their switches in E coli using the same repressors as Elowitz and Leibler.
A curated version of the toggle switch in different formats from BioModels Database (BIOMD0000000507)
Both papers became milestones in synthetic biology (as witnessed by over 2000 citations each according to Google scholar as of January 2014). The model they describe are also classic examples used in biological modelling courses to explore oscillatory and multistable systems, simulated by deterministic and stochastic approaches.