Now more than ever, it’s in the synthetic biologist’s DNA to make cheap, high-quality, highthroughput (HTP) synthetic genes available for applications in research and biotechnology. Two new reports, both connected to the laboratory of George Church, HMS professor of genetics and recipient of the 2010 Bower Award, describe innovative technological advances to do just that.
The costliest steps during gene synthesis include the initial step of oligonucleotide (oligo) synthesis and final step of sequencing the assembled product. In the December 2010 issue of Nature Biotechnology, the authors detailed methods to drive down the costs of gene synthesis by ten-fold to less than one cent per nucleotide. First, researchers replaced traditional, expensive column-derived oligos with inexpensive HTP microarray-based oligos of improved accuracy. Second, the authors report two approaches to improve the quality of the microassay oligos. Sriram Kosuri, a postdoctoral fellow in Church’s laboratory, and team extracted, or amplified, specific oligos from the heterogeneous pool by PCR prior to gene assembly, while Mark Matzas of the German biotech Febit and collaborators used preselected oligos for assembly into larger genes. Finally, researchers significantly reduced error rates by synthesizing microarray oligos as long as 200 bases.
Despite these advances in cost and accuracy, the synthesis of ‘difficult’ sequences still poses a challenge. Nevertheless, these latest milestones will make it possible to synthesize larger genes, genomes and libraries faster and cheaper.
For more information, students may contact George Church at gmc@harvard.edu.
Conflict Disclosure: George Church is a co-founder of an early-stage startup company involved in gene synthesis; Sriram Kosuri, Nikolai Eroshenkoare and George Church named inventors on a patent application on technologies described in the study. Sriram Kosuri. is a post-doctoral fellow whose future employment prospects depend upon refereed publications.
Funding Sources: This research was supported by the U.S. Office of Naval Research, the National Human Genome Research Institute Center for Excellence in Genomics Science, the Department of Energy, the Defense Advanced Research Projects Agency and the Wyss Institute for Biologically Inspired Engineering; the authors are solely responsible for the content of this work.
