## 4 Future Perspectives: Expanding the Natural Horizon
### Synthetic Biology  
Parallel to the advances in biodiscovery and natural product chemistry have been the developments in synthetic biology, whereby synthesis and synthetic manipulation of natural products has superseded the need for biological production. Indeed, it has recently been proposed that synthetic biology is poised to reinvigorate interest in natural products as sources of new antibiotics [124, 125, 126]. Synthetic biology, described as the application of rational engineering processes to biological systems, has replaced the prior approach of random and laborious manipulation of genetic information encoded in biosynthetic genes. Once the biosynthetic pathways are understood, from the individual components to the sum of the parts, synthetic biology can format a production line in a targeted fashion to generate libraries of structurally similar compounds which can then be screened for favorable activities. In a form of directed evolution, it can significant accelerate the process of bio-discovery, and in just a few years the synthetic biology approach and concepts have moved from an avant-garde concept to a solid and powerful reality [127]. In addition, genetic manipulation of producing organisms or heterologous hosts has the demonstrated potential to prime the metabolic network for increased production of sought after secondary metabolites [128]. Described in some studies as a form of \"plug and play\", synthetic biology will ultimately allow us to integrate newly sequenced pathways into pre-engineered microbial hosts primed for the overproduction of compounds synthesized from specific pathway classes [124]. From a synthetic biology perspective, marine BGCs represent an almost inexhaustible resource for the synthesis of new metabolites [129; 130; 131]. Most of the BGCs are characterized by a high degree of modularity (e.g., PKS, NRPS). This characteristic allows both the refactoring of genes belonging to a specific cluster and combination of specific modules among clusters. Such approaches can lead to both an increase in yield of a specific metabolite and to the synthesis on new non-native compounds [124; 132]. One outstanding example is the pioneering work of [PERSON] and co-authors that, combining plant and bacteria derived genes, were able to engineer both _E. coli_ and _S. cerevisiae_ to produce amorphadiene and artemisinin acid, precursors of the potent antimalarial drug artemisinin extracted with laborious procedures and low yields from the plant _Artemisia annua_[133; 134; 135; 136]. The power of this approach was recently shown in a study that led to the discovery of 74 novel compounds produced using a combinatorial genetic approach in yeast [137]. Interestingly, \(>\)75% of the identified molecules have not been described previously. The great phylogenetic diversity of marine microorganisms together with the astonishing biosynthetic diversity emerged from the recent development of the sequencing technology are already giving new hope for the identification of new valuable chemical products. The biological features of the known biosynthetic systems represent rich toolbox that can produce an inestimable chemical diversity [124]. The synthetic biology approach might present in the near future the necessary keystone to explore such diversity. However, the undoubted potential of this technology currently comes at a price, and the complexity of BGCs [138] ensures that synthetic biology will not replace the biological approach, at least for the foreseeable future. Refactoring BGCs via a synthetic biology approach is highly resource intensive, bearing in mind the large size of most secondary metabolic gene clusters (multiple genes at a typical length of 20-150 kb). Taking into account current gene synthesis costs, the technical challenges involved in homologous recombination based assembly of gene clusters, and the likely requirement for generating multiple cluster variants, the cost per compound could be as high as $50K USD or more per compound [139].