Increasing the Scalability of DNA Synthesis and Its Key Role in Expanding the Biopharmaceutical Discovery Process

DNA synthesis is a naturally occurring process that happens during DNA replication. In the mid-twentieth century, a chemical process was developed to synthesize single-stranded oligonucleotides. By the early 1980s, multiple commercial companies were selling synthetic DNA. Gene synthesis (i.e., DNA assembly) methods were developed in parallel to generate long double-stranded DNA (dsDNA) fragments from many short, synthetic oligonucleotides. These classical methods have been improved upon and miniaturized over the past few decades, culminating in modern gene synthesis platforms that can simultaneously synthesize ~10,000 genes where legacy gene synthesizers could synthesize only one. In this chapter, we review the key advances that enabled modern-scale gene synthesis and how they set the stage for an expanded role for synthetic gene fragments in antibody biopharmaceutical development. We conclude that, in this world of nearly unlimited gene synthesis capacity, the test and learn phases of the design-build-test-learn cycle have supplanted the build phase as the new bottlenecks in biopharmaceutical development.