Frances H. Arnold won half of the 2018 prize for directing evolution in a test tube, speeding up the natural selection of the most productive enzymes to drive chemical reactions. The other half of the prize went to George P. Smith and Sir Gregory P. Winter: Smith figured out how to use viruses to produce new proteins with particular properties; Winter took that general idea and used it to focus the evolution of antibodies—proteins that are key to helping the body fight disease. Arnold is at the California Institute of Technology, and will take home half of the roughly $1-million prize. Smith is at the University of Missouri—Columbia, and Winter is at the MRC Laboratory of Molecular Biology in England. They will split the other half of the money.
All three scientists took Charles Darwin’s idea of natural selection, in which molecules or organisms accumulate mutations in a slow, random process, and figured out ways to identify and select specific mutations that improve the ability of molecules such as proteins and enzymes—workhorses that cells use to carry out all their basic functions—to attach to and change still other molecules. By picking and choosing enzymes with improved abilities and repeatedly refining them, Arnold ended up with one that performed 256 times better than the original.
“This was a revolution based on evolution,” says Claes Gustafsson, a member of the Nobel Committee for Chemistry. Sara Snogerup Linse, another member, says that thanks to the work Arnold pioneered, “now you can use these enzymes to speed up reaction and to replace toxic chemicals.”
Arnold, who began her line of research in the early 1990s, becomes only the fifth woman to win the chemistry Nobel, out of 168 winners overall. In a speech several years ago she said the notion of improving on the natural course of evolution was an idea that needed to come from an outsider. “Twenty-five years ago it was considered the lunatic fringe,” Arnold said in 2014, when she was inducted into the National Inventors Hall of Fame. “Scientists didn’t do that. Gentlemen didn’t do that. But since I’m an engineer and not a gentleman, I had no problem with that.”
Smith’s research, begun in the 1980s, utilized a bacteriophage—a type of virus that infects bacteria and can be coopted into carrying different types of genes. Genes code for proteins, and Smith got his phages to display those proteins on their outer coats. He then used antibodies, which only bind to very specific targets, to fish out the proteins he was interested in. This process is called phage display. The ability to select specific proteins, cycle their genes back through the phage, and again fish out the best ones sped up natural selection.
Winter flipped this idea around. He put the genes for antibodies inside phages, got the phages to produce antibodies on their coats, and used a small molecule to fish out only antibodies that had a particular kind of binding site. Binding sites are how antibodies latch onto disease-causing molecules in the body, so Winter had developed a way of producing highly efficient antibodies in a short period of time. Because of this, Linse says, “now we can use antibody drugs with greater efficiency and fewer side effects.” Of the 15 most-sold drugs on the planet, she says, 11 are now made by processes based on this method.