Essay Precision Genome Engineering and Agriculture: Opportunities and Regulatory Challenges Daniel F. Voytas 1 *, Caixia Gao 2 * 1 Department of Genetics, Cell Biology, and Development and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota, United States of America, 2 State Key Laboratory of Plant Cell and Chromosome Engineering, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China Abstract: Plant agriculture is poised at a technological inflection point. Recent advances in genome engineering make it possible to precisely alter DNA sequences in living cells, providing unprecedent- ed control over a plant’s genetic material. Potential future crops derived through genome engineer- ing include those that better with- stand pests, that have enhanced nutritional value, and that are able to grow on marginal lands. In many instances, crops with such traits will be created by altering only a few nucleotides among the billions that comprise plant genomes. As such, and with the appropriate regulato- ry structures in place, crops created through genome engineering might prove to be more acceptable to the public than plants that carry foreign DNA in their genomes. Public perception and the perfor- mance of the engineered crop varieties will determine the extent to which this powerful technology contributes towards securing the world’s food supply. This article is part of the PLOS Biology Collection ‘‘The Promise of Plant Translational Research.’’ Over the past 100 years, technological advances have resulted in remarkable increases in agricultural productivity. Such advances include the production of hybrid plants and the use of the genes of the Green Revolution—genes that alter plant stature and thereby increase productivity [1,2]. More recently, transgenesis, or the introduction of foreign DNA into plant genomes, has been a focus of crop improvement efforts. In the US, more than 90% of cultivated soybeans and corn contain one or more transgenes that provide traits such as resistance to insects or herbicides [3]. Transgenesis, however, has limitations: it is fundamentally a process of gene addition and does not harness a plant’s native genetic repertoire to create traits of agricultural value. Furthermore, public concerns over the cultivation of crops with foreign DNA, particularly those generated by the intro- duction of genes from distantly related organisms, have impeded their widespread use. The regulatory frameworks created to protect the environment and to address public safety concerns have added consid- erably to the cost of transgenic crop production [4]. These costs have limited the use of transgenesis for creating crops with agriculturally valuable traits to a few high-profit crops, such as cotton, soybean, and corn. The tools of genome engineering allow DNA in living cells to be precisely manipulated (reviewed in [5]). Although genome engineering can be used to add transgenes to specific locations in ge- nomes, thereby offering an improvement over existing methods of transgenesis, a more powerful application is to modify genetic information to create new traits. Traditionally, new traits are introduced into cultivated varieties through breeding regimes that take advantage of existing natural genetic variation. Alternatively, new genetic variation is created through mutagenesis. With genome engineering, it is possible to first determine the DNA sequence modifications that are desired in the cultivated variety and then introduce this genetic variation precisely and rapidly. The ability to control the type of genetic variation introduced into crop plants promises to change the way new varieties are generated. Already genome engineer- ing is being used in crop production pipelines in the developed world, and this technology can also be used to improve the crops that feed the burgeoning popu- lations of developing countries. The Technological Underpinnings of Genome Engineering Genome engineering is enabled by harnessing the cell’s DNA repair pathways (reviewed in [5]). Most genome engineer- ing techniques direct the repair of DNA double-strand-breaks (DSBs), which are introduced in the genome at or near the Essays articulate a specific perspective on a topic of broad interest to scientists. Citation: Voytas DF, Gao C (2014) Precision Genome Engineering and Agriculture: Opportunities and Regulatory Challenges. PLoS Biol 12(6): e1001877. doi:10.1371/journal.pbio.1001877 Academic Editor: Susan R. McCouch, Cornell University, United States of America Published June 10, 2014 Copyright: ß 2014 Voytas, Gao. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work has been funded by a grant from the National Science Foundation to DFV (DBI 0923827) and grants to CG from the National Natural Science Foundation of China (31271795) and the Ministry of Agriculture of China (2014ZX0801003B). The funders had no role in the decision to publish or preparation of the manuscript. Competing Interests: D.F.V. is an inventor on several patents concerning TAL effector-mediated DNA modification and serves as Chief Science Officer for Cellectis Plant Sciences, a biotechnology company that uses sequence-specific nucleases to create new crop varieties. Abbreviations: CRISPR, clustered regularly interspersed short palindromic repeats; HR, homologous recombination; NHEJ, non-homologous end-joining; SSN, sequence-specific nuclease; TALEN, transcription activator-like effector nuclease; ZFN, zinc-finger nuclease. * E-mail: voytas@umn.edu (DFV); cxgao@genetics.ac.cn (CG) PLOS Biology | www.plosbiology.org 1 June 2014 | Volume 12 | Issue 6 | e1001877