Scientists from UNC School of Medicine have invented a powerful new 'direct evolution' technique for the rapid development of scientific tools and new treatments for many diseases. The team published their breakthrough in Cell, and it demonstrated the method by evolving several proteins to perform precise new tasks, each time doing it in a matter of days. Previous existing methods of direct evolution are more complicated and time-consuming and are typically applied in bacterial cells, which limits the usefulness of this technology for evolving proteins for use in human cells.
Directed evolution is artificial, sped up version of the evolution process in nature. The concept is to focus the evolutionary process on a single DNA sequence to make it perform a specified task. In principle, they can use directed evolution to produce new therapeutics that work powerfully to stop diseases and have a few or no side effects. The initial groundbreaking scientific work on directed evolution won the 2018 Nobel Prize in Chemistry.
A post-doctoral research associate in the Department of Pharmacology at the UNC School of Medicine, Justin English, the lead author of the study, said that what they have developed is the most robust system yet for directed evolution in mammalian cells.
According to the senior author of the study, Bryan L. Roth, MD., Ph.D., the Michael Hooker Distinguished Professor in the Department of Pharmacology at the UNS School of Medicine, the scientific community has needed a tool like this for a long time. They believe their technique will accelerate research and ultimately lead to better therapeutics for individuals suffering from many of the diseases for which they need much better treatments.
Roth, English, and their colleagues developed the new method, and it is comparatively quick, easy, and versatile. It uses the Sindbis virus as the carrier of the gene to be modified. With its genetic cargo, the virus can infect cells in a culture dish and mutate quite rapidly. The team set up conditions so that the only mutant genes to thrive are the ones encoding proteins capable of accomplishing the desired function within the cells, including activating a specific receptor or switching on individual genes. Since the system works in maintaining cells, it can be used to evolve new human, mouse, or other mammalian proteins that would be burdensome or impossible to generate with traditional bacterial cell-based methods.
The researchers revealed the potential of VEGAS, in their final demonstration, 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.