Scaling Up DNA Computing with Array-Based Synthesis and High-Throughput Sequencing

Abstract It was 40 years ago today, when Ned taught DNA to play [32]. When Ned Seeman began laying the theoretical foundations of what is now DNA nanotechnology, he likely did not imagine the entire diversity and scale of molecular structures, machines, and computing devices that would be enabled by his work. While there are many reasons for the success of the field, not least the creativity shown by Ned and the community he helped build, such progress would not have been possible without breakthroughs in DNA synthesis and molecular analysis technology. Here, we argue that the technologies that will enable the next generation of DNA nanotechnology have already arrived but that we have not yet fully taken advantage of them. Specifically, we believe that it will become possible, in the near future, to dramatically scale up DNA nanotechnology through the use of array-synthesized DNA and high-throughput DNA sequencing. In this article, we provide an example of how DNA logic gates and circuits can be produced through enzymatic processing of array-synthesized DNA and can be read out by sequencing in a massively parallel format. We experimentally demonstrate processing and readout of 380 molecular gates in a single reaction. We further speculate that in the longer term, very large-scale DNA computing will find applications in the context of molecular diagnostics and, in particular, DNA data storage.