Harvard scientists perform rapid prototyping on bacteria

Scientists at Harvard Medical School have developed a rapid-prototyping technique for cells intended to make the process of optimising chemical production from bacteria and other low-level organisms much more quickly.

A combination of robotics and a novel method for inserting multiple DNA strands into a genome at once forms the basis of the Multiplex Automated Genome Evolution (MAGE) system developed by graduate student Harris Wang and postdoctoral researcher Farren Isaacs in Professor George Church’s lab at Harvard.

“Our approach involves a nice synergy between engineering and evolution,” claimed Isaacs, noting that the technique used for a paper published online by Nature in late July relies on the combination of targeted genetic changes working in combination with the generation of a huge number of random variations, finally selecting cells with the desired behaviour.

By deliberately knocking out certain genes and trying out many different sequences in a part of the gene used by Escherichia coli bacteria to produce a protein that makes the industrial chemical lycopene, the researchers realised a five-fold increase in efficiency within just three days. Up to 24 pieces of DNA, each around 90 bases long, were replaced simultaneously in the target bacteria, with more than 4 billion subtly different mutants produced each day. From those, Isaacs and Wang were able to pick the best performers.

Although the key to MAGE is the way in which many different short strands of DNA can be inserted into cells, automation equipment is used to cycle through the seven major steps of heating, chilling and mixing that the full system needs. “We have prototype devices but we are trying to make them more robust and so we are working with some industrial partners on that,” said Isaacs. “Automation will enhance our ability to do these experiments 24/7 as well as improve our ability to develop the technology further and hopefully commercialise it.”

Repeated cycling with the same pool of DNA strands reduces the number of variants that remain in the growth chambers until they converge on one. This aspect of MAGE is being used in an attempt to alter the genetic code that cells use to make proteins. “That is a much bigger project and is now very close to being completed,” said Isaacs.

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