'Lab evolution of biomolecules may yield new class of drugs'

The Harvard University research, published in the journal Nature, could ultimately allow the tailoring of custom pharmaceuticals and research tools from lab-grown proteins, nucleic acids, and other such compounds.

According to the researchers, the new approach dubbed phage-assisted continuous evolution, or PACE, is 100 times faster than the conventional laboratory evolution and far less labour-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 Dr David Liu, a Harvard professor of chemistry and chemical biology who led the research.

"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 his Harvard colleagues 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 separate 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.

Evolution of biomolecules is also a natural process, of course, but during biological evolution generation times tend to be very long and researchers have no control over the outcomes.

Laboratory evolution (also called directed evolution) has been practiced for decades to generate biomolecules with tailor-made properties, but it has been very complex and time consuming.

"Laboratory evolution has generated many biomolecules with desired properties, but a single round of mutation, gene expression, screening or selection, and replication typically requires days or longer with frequent human intervention," the researchers wrote.

"Since evolutionary success is dependent on the total number of rounds performed, a means of performing laboratory evolution continuously and rapidly could dramatically enhance its effectiveness.