Synthetic biology to access and expand nature's chemical diversity

Key Points This Review covers the recent advances in synthetic biology and how these advances will affect the field of natural products. There has been an emphasis on creating genetic parts, such as promoters, that generate precise levels of gene expression. The generation of large libraries of well-characterized parts and the development of biophysical and bioinformatic models to predict the behaviour of genetic parts in different organisms will aid in the transfer of biosynthetic gene clusters between hosts. The capacity of DNA synthesis has exploded over the past decade and it is routine to synthesize the 20–100 kb required for a large gene cluster. In addition, new DNA assembly methods enable the rapid construction of different genetic part permutations or to substitute many genetic parts in a single step. With regard to synthetic regulation, genetic circuits have been constructed that function as logic gates, timers, switches and oscillators. Sensors have also been developed that respond to many inducible inputs as well as metabolite levels. These could be incorporated into natural product pathways to control the timing of expression of different genes or to implement feedback in response to a toxic intermediate. It is often desirable to make many simultaneous genomic changes. Methods such as CRISPR–Cas9 can target essentially any region of the genome and have been shown to function in many species, including several host species that are well suited for the industrial-scale production of small molecules. Advances in synthetic biology have simplified the characterization and production of biologically active molecules from various organisms. In this Review, Voigt and colleagues outline the design and construction of pathways used for the synthesis of such natural products in host microorganisms. Bacterial genomes encode the biosynthetic potential to produce hundreds of thousands of complex molecules with diverse applications, from medicine to agriculture and materials. Accessing these natural products promises to reinvigorate drug discovery pipelines and provide novel routes to synthesize complex chemicals. The pathways leading to the production of these molecules often comprise dozens of genes spanning large areas of the genome and are controlled by complex regulatory networks with some of the most interesting molecules being produced by non-model organisms. In this Review, we discuss how advances in synthetic biology — including novel DNA constructi