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Harvard Scientists Pioneer High-Speed Gene Tweaking Method

In the new issue of Nature, published online July 26, a team of researchers working out of George Church‘s lab at Harvard Medical School describes a new cell programming method called Multiplex Automated Genome Engineering (MAGE) that promises to be a transformational technology for the field of synthetic biology.

Currently, genetic engineers use a linear process to modify the DNA of single-celled organisms — usually E. coli. or yeast strains — painstakingly isolating, breaking up, reassembling, and reinserting sections of DNA to modify and maximizes the organism’s functionality for a given task, say, increasing the output of particular chemical compound. Even as DNA sequencing — the “reading” side of modern genetics research — gets faster and faster, the “writing” or editing part that synthetic biologists are focused on remains time-consuming and labor-intensive, requiring the construction of version after version of an engineered bacterium, tweaking one gene at a time to attain incremental improvements in performance.

Harris Wang of Harvard

Harris Wang of Harvard

In contrast, the technique developed by the Harvard team, led by Harris Wang and Farren Isaacs, allows researchers to edit multiple genes in parallel, dramatically speeding up the pace of in-lab evolution. From the Harvard Medical School press release describing the study:

“The researchers selected a harmless strain of the intestinal nemesis E. coli and added a few genes to its solitary circular chromosome, coaxing the organism to produce lycopene, a powerful antioxidant that occurs naturally in tomatoes and other vegetables. Now they could focus on tweaking the cells to increase the yield of this compound…”

The team focused on 24 genes known to affect lycopene production, dividing them into manageable 90-letter segments and modifying them to generating a suite of thousands of genetic variants. Next, they sent the sequences out to a company that synthesized the DNA sequences, and then they reinserted them back into the cells. From the resulting pool of genetically modified cells, the researchers extracted the best producers (because lycopene turns the cells red, the researchers could simply select the brightest bacteria) and repeated the process over and over to hone the cells’ manufacturing machinery, automating their process for greater efficiency. (Wired Science has an illustration of the process.)

The result: Within three days, the team had generated some 15 billion genetic variants and increased the yield of lycopene by 500 percent,  “a significant improvement over existing metabolic engineering techniques,” write the study’s authors. To illustrate the exponential gain in efficiency, Wang and Isaacs, quoted in the New Scientist, point out that DuPont spent nearly seven years and hundreds of millions of dollars to identify 20 genetic changes that optimize microbes to produce a chemical called 1,3-propanediol, which is used as a commercial solvent. The new approach can create hundreds or thousands of mutations in a few days at a cost of a few thousand dollars.

The New Scientist reports that the team is planning to adapt the technique to yeast soon, and that it should also work with plant and animal cells. The researchers are already teaming up with biofuels and chemical manufacturers to explore industrial applications.

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