As a result, scientists could generate an enzyme with a tailor-made target activity in a single week—through as many as 200 rounds of protein evolution—a feat that Liu says might have taken years with conventional methods.
Liu and his colleagues developed PACE with accessibility in mind; the system can be built from readily available components. He believes it could one day be used to rapidly evolve highly potent and specific therapeutic antibodies—a promising new treatment avenue for cancer and autoimmune diseases. While current directed evolution methods are capable of producing such molecules, they are sometimes prohibitively time-consuming and expensive.
And it also opens the door to addressing some long-standing basic questions about how molecular evolution works. With the PACE setup, researchers can simultaneously run the same evolutionary experiment many times and for many generations, investigating whether a particular protein will always follow the same evolutionary trajectory under a given set of conditions. With conventional methods, this kind of investigation might take decades; with PACE, it can be done in two weeks. “To me, it’s extremely interesting to be able to do experiments like that,” says Frances Arnold, a professor of chemical engineering, bioengineering, and biochemistry at Caltech. “It leaves me eager to see the results.” Arnold was not involved in the study.
She cautions, however, that certain macromolecules won’t be amenable to the new approach. For a protein or nucleic acid to be a target for PACE, it needs to be linkable to the survival of the virus. Because of this quirk, says Arnold, the system’s practical utility is somewhat limited—it couldn’t, for example, design an enzyme for use in biofuel production. Nonetheless, says Arnold, “it’s a very clever application to do continuous evolution of a limited set of proteins.”