Engineering development: From the repressilator and toggle switch to synthetic developmental biology

The publication of two landmark papers in the year 2000 demonstrated that scientists could rationally engineer genetic circuits to perform desired biological processes commonly found in nature. Elowitz and Leibler constructed a repressilator based on a negative feedback loop that showed oscillatory behavior, and the Collins lab engineered a toggle switch that was able to switch between and maintain stable states in response to external stimuli. Although built upon a long history of conceptual and technical advances in the field, both studies were nevertheless instrumental in transforming the way investigators studied complex biological processes. Rather than using a top-down approach to dissect and analyze individual components of biological processes, both research teams employed a bottom-up approach, creating genetic devices that reconstructed fundamental cellular processes-in essence, building to understand. As described in this review, this bottom-up approach was particularly transformative in the field of developmental biology where the "build to understand" approach yielded important insights into long-standing problems in developmental biology: the mechanisms underlying promiscuous, combinatorial signaling; how cells acquire a stable fate; and the emergence of complex patterns. Additionally, these papers laid the foundation for an array of technical advances that spawned the field of synthetic developmental biology and its fruitful applications to tissue engineering and regenerative medicine.