Editorial overview: Engineering and design: raising the bar through innovation and integration.

Engineering of specific binding proteins de novo using immunoglobulin and non-immunoglobulin scaffolds is a mature field that has already produced numerous molecules of high practical impact. Jost and Plückthun review recent developments in the design strategies of scaffolds and combinatorial libraries. They find that, whereas early studies heavily depended on bruteforce directed evolution technologies and minimally utilized structural information, recent studies tightly integrate directed evolution technologies with knowledge gained from structural analyses of engineered interfaces and/or computational design. These strategies, necessarily tailored for specific scaffolds and for specific classes of targets, have essentially solved the challenge of generating specific and tight binding proteins against diverse water-soluble molecules. Intense interest in bispecific binding proteins has stimulated development of engineered immunoglobulin scaffolds primarily through interface redesign. The simple architecture and high designability of non-immunoglobulin scaffolds allows for bottom-up approaches to the construction of higher-order molecules. It is tempting to argue that the collective capability of the field now exceeds that of natural systems (e.g. the immune system) and that the remaining challenges in this field are more quantitative and target-dependent, such as achieving the right levels of affinity and specificity to the right epitope for optimal outcomes.