Multiplex Automated Genomic Engineering (MAGE)
A machine that speeds up evolution is revolutionizing genome design
A new tool for synthetic biology
We are in the midst of a genomic revolution, and are becoming more adept at sequencing ("read") and synthesizing ("write") the DNA that makes up genomic information. However, current techniques for writing genomes are laborious and painstaking, and predicting phenotype from genotype is difficult because biological systems are so extraordinarily complex and interconnected. Instead of trying to build genomes from scratch, George Church and researchers at the Wyss Institute have created MAGE, a machine that harnesses the natural principles of evolution to do all the heavy lifting of genome design and automates these steps to dramatically shorten the time scale. Billions of different mutant genomes can now be generated per day. Mutants of interest are kept, and mutants that do not have the desired properties are discarded. This is rapid prototyping on a massive scale.
How MAGE works
Using allelic replacement, a pool of targeting oligos is repeatedly introduced into a cell. MAGE can successfully introduce new genetic modifications in about 25% of the cell population, creating billions of variants every 3 hours. Not only can MAGE simultaneously modify multiple genomic locations across different length scales (i.e., from single nucleotides to whole genes), it is also possible to tune the amount of sequence change per target. This makes it possible to make specific modifications for specific outcomes or to make high-diversity modifications to explore sequence space. After allelic replacement, cells are assayed for genotype and/or phenotype analysis and the cycle repeats with the subset of cells that contain genomic sequences of interest.
The MAGE device can perform up to 50 different genome alterations at nearly the same time, producing combinatorial genomic diversity. In one instance, Church and Wyss researchers were able to make the bacteria Escherichia coli (E. coli) synthesize five times the normal quantity of lycopene, an antioxidant, in a matter of days and just $1,000 in reagents.
The speed and ease with which MAGE can alter genomes will transform how we approach the manufacturing and production optimization of industrially significant compounds in the bioenergy, pharmaceutical, agricultural, and chemical industries.
Wang, H, Isaacs, F, Carr, P, Sun, Z, Xu, G, Forest, C, & Church, G 2009, Programming cells by multiplex genome engineering and accelerated evolution, Nature, 460, 7257, pp. 894-898.