Much faster directed evolution of proteins could speed development of molecular machine systems

One of the principal recommendations of the Technology Roadmap for Productive Nanosystems was to “Support the development of modular molecular composite nanosystems (MMCNs)” (see Productive Nanosystems: A Technology Roadmap, page 12 of 198-page PDF) in which large DNA frameworks (of the sort that we cited last week) are to be used to support relatively rigid functional objects of engineered proteins. Such proteins could be engineered through either rational design or directed evolution (for an excellent update on the latter see this post by Eric Drexler on Metamodern from October 2010). Laboratory-directed evolution can, however, be laborious, so anything to make it faster and easier might substantially advance this approach. Now ScienceDaily points to this Harvard Gazette article by Steve Bradt that announces a major improvement “Speeding up biomolecular evolution: New approach proves 100 times faster than before“:

Scientists at Harvard University have harnessed the prowess of fast-replicating bacterial viruses, also known as phages, to accelerate the evolution of biomolecules in the laboratory. The work, reported in the journal Nature [abstract], could ultimately allow the tailoring of custom pharmaceuticals and research tools from lab-grown proteins, nucleic acids, and other such compounds.

The researchers, led by Professor David R. Liu, say that their approach — dubbed “phage-assisted continuous evolution,” or PACE — is roughly 100 times faster than conventional laboratory evolution, and far less labor-intensive for scientists.

“Most modern drugs are based on small organic molecules, but biological macromolecules may be better suited as pharmaceuticals in some cases,” said Liu, a professor of chemistry and chemical biology at Harvard and an investigator with the Howard Hughes Medical Institute. “Our work provides a new solution to one of the key challenges in the use of macromolecules as research tools or human therapeutics: how to rapidly generate proteins or nucleic acids with desired properties.”

Liu and Harvard co-authors Kevin M. Esvelt and Jacob C. Carlson achieved up to 60 rounds of protein evolution every 24 hours by linking laboratory evolution to the life cycle of a virus that infects bacteria. This phage’s life cycle of just 10 minutes is among the fastest known. Because this generation time is so brief, the phage makes a perfect vehicle for accelerated protein evolution. The PACE system uses E. coli host cells to produce the resulting proteins, to serve as factories for phage production, and to perform the key selection step that allows phage-carrying genes encoding desired molecules to flourish.

In three protein evolution experiments, PACE was able to generate an enzyme with a new target activity within a week, achieving up to 200 rounds of protein evolution during that time. Conventional laboratory evolution methods, Liu said, would require years to complete this many rounds of evolution. …

It remains to be seen just how general this method will be since it depends on linking the activity to be evolved to protein production in bacteria. Nevertheless, it looks like the individual components of MMCN development are progressing nicely. Perhaps the next challenge is to see if the pieces can be put together to make effective molecular machine systems, leading eventually to atomically precise productive nanosystems.

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