One of the most astounding findings of the human genome project was that our genomes contained as many genes as that of Drosophila melanogaster.
This finding begged the question: how do you get one organism to look like a fly and another like a human with the same number of genes? One possibility is that the rich repertoire of non-protein coding sequence found in the genomes of complex organisms adds many new parts with which to generate complexity1
. A decade of research has put forward the rather different idea that instead of looking at the length of the parts list as the determinant of organismal complexity, we should look at how those parts fit together2,3
. From this perspective, complexity arises from novel combinations of pre-existing proteins and the ability to evolve new phenotypes rests on the MODULARITY of biological parts.
While natural examples have been found to illustrate this latter possibility3
, strong evidence to support this post-genomic view of biology has come from the synthesis of new biological systems. Rational synthesis of biological systems can hint at the natural history of how a particular system came to acquire its properties4,5
. More often, however, we use synthetic circuits to explore, in a hands-on fashion, the set of design principles that determine the structure and operation of biological systems.
The core aim of synthetic biology is to develop and apply engineering tools to control cellular behavior, using precisely characterized parts, such as cis
-regulatory elements, to achieve desired functions. An important direction, for example, has been to engineer cells with an eye towards practical applications, such as BIOREMEDIATION6
, and even the beginnings of clinical applications10–12
. In this Review, however, we focus on how synthetic circuits help us to understand how natural biological systems are genetically assembled and how they operate in organisms from microbes to mammalian cells. In this light, synthetic circuits have been critical as simplified test-beds in which to refine our ideas of how similarly structured natural networks function and have served as tools to control natural networks. We highlight the contribution of synthetic biology to putting together an increasingly quantitative description of gene expression and signal transduction, in uncovering the diversity of behaviors that can arise from positive and negative feedback systems, and progress in rationally controlling spatial organization and cell-cell interactions. We pay particular attention to recent progress in using synthetic systems to uncover novel aspects of cell biology, such as how cells decide to undergo apoptosis and the molecular basis for communication between the endoplasmic reticulum and mitochondrion. We aim to show that synthetic biological approaches have given us a great deal of intuition on how the simple building blocks that underlie complex natural systems work as well as basic tools to quantitatively characterize natural phenomena, both of which are crucial for the field to progress into the analysis and complete control of natural circuits.