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Researchers develop directed evolution technique

New method for directed evolution could improve gene therapies and generic drug development.

Researchers have created a new “directed evolution” technique for the rapid progression of scientific tools. According to the developers, the technique could be used in gene therapies and to improve generic drug development.

The researchers were able to evolve several proteins to perform precise new tasks, each time doing it in a matter of days. Existing methods of directed evolution are time-consuming and are typically applied in bacterial cells, which limits the usefulness of this technology for evolving proteins for use in human cells.

“What we have developed is the most robust system yet for directed evolution in mammalian cells,” said study lead author Dr Justin English.

The method uses the Sindbis virus as the carrier of the gene to be modified. The virus with its genetic cargo can infect cells in a culture dish and mutate quite rapidly. The researchers set up conditions so that only mutant genes which encoded proteins capable of accomplishing a desired function within the cells thrived.

The new system was named “VEGAS” for Viral Evolution of Genetically Actuating Sequences. In an initial demonstration, the lab modified a protein called a tetracycline transactivator (tTA), which works as a switch to activate genes. Usually tTA stops working if it encounters the antibiotic tetracycline or closely related doxycycline, but the researchers evolved a new version with 22 mutations that allowed tTA to keep working despite very high levels of doxycycline.

The scientists next applied VEGAS to a common type of cellular receptor called a G protein-coupled-receptor (GPCR). There are hundreds of different GPCRs on human cells. VEGAS quickly mutated a little-studied GPCR called MRGPRX2 so that it would stay permanently active.

In a final demonstration, the team showed the potential of VEGAS to guide drug development more directly. They used VEGAS to rapidly evolve small biological molecules called nanobodies that could activate different GPCRs – including serotonin and dopamine receptors, which are found on brain cells and are targeted by many psychiatric drugs.

The team is now using VEGAS to develop highly efficient gene-editing tools, potentially for curing genetic diseases and to engineer nanobodies that can neutralise cancer-causing genes.

The findings were published in Cell.

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