Three scientists who put evolution to work in the lab have won the Nobel Prize in Chemistry.
Frances Arnold of the California Institute of Technology in Pasadena was awarded half of the $1 million prize for her work on the “directed evolution” of enzymes, proteins that catalyze specific chemical reactions. The enzymes that resulted from her research have made it possible to develop new ways to make key pharmaceuticals and more environmentally friendly processes for making industrial chemicals. George Smith of the University of Missouri in Columbia and Gregory Winter of the Medical Research Council’s Laboratory of Molecular Biology (LMB) in Cambridge, U.K., share the other half of the award for their research on the directed evolution of antibodies, proteins the immune system uses to recognize invaders. Their findings enabled large-scale production of specific antibodies, which have made new treatments possible for autoimmune diseases, cancer, and other conditions.
“This year’s prize in chemistry rewards a revolution based on evolution,” Claes Gustafsson, chair of the Nobel Committee for Chemistry, said this morning. “Our laureates have applied the principles of [Charles] Darwin in the test tubes, and used this approach to develop new types of chemicals for the greatest benefit of humankind.”
In the 1990s, Arnold was the first to demonstrate how to use directed evolution to produce new enzymes. Her team would start with an enzyme that exists in nature and isolate the gene that encodes it; then, they used different techniques to introduce mutations into the gene and reinsert the new variants into bacteria. The bacteria would produce a variety of new enzymes, which the researchers screened for the qualities they desired, such as the ability to work faster or under challenging conditions, such as high temperatures or the presence of chemicals. They collected the bacteria that produced the desired enzymes and started the process over again, looking for an even better enzyme.
Arnold, a chemical engineer, says many scientists didn't immediately embrace the idea of making huge numbers of new randomly changed protein variants. "The industrial people, the people who had to make better proteins, said, 'Yeah, this makes total sense.' The people who wanted to understand proteins were aghast. They said, 'That’s not science.' I said, 'Well, I’m an engineer!' The paradigm at the time was, you get a structure of a protein, you use your big brain to figure out what mutations to make, you go and make those, you see it doesn’t work. … Only engineers would do something like random mutagenesis."
Using this method, researchers have been able to produce enzymes that catalyze reactions that don’t exist in nature. That made it possible to develop, for example, new kinds of fuels derived from plants, new processes for making industrial chemicals without toxic metals or organic solvents, and new pharmaceuticals. Many of these useful variants likely would not have been found without the random mutagenesis strategy, says Arnold, the first woman, and eighth living scientist to be elected to all three of the U.S. National Academies of Sciences, Engineering, and Medicine. "We found beneficial mutations [that made better proteins] immediately. When we went and mapped those to the protein structures, we realized nobody could predict them. … Beneficial mutations that affect function were spread out all over the protein. We couldn’t even explain them much less predict them. That’s unfortunately still true today.”
Our laureates have applied principles of [Charles] Darwin in the test tubes, and used this approach to develop new types of chemicals for the greatest benefit of humankind.
The other two winners, Smith and Winter, also found ways to harness evolution and microorganisms to produce desired proteins—in their case, antibodies instead of enzymes. Antibodies are proteins the immune system produces to recognize foreign invaders and mark them for attack. Scientists use them in a huge variety of ways to recognize and identify specific proteins.
In the 1980s, Smith described a way to use phages, viruses that infect bacteria, to make pieces of specific proteins and “display” them on their surface. This enabled scientists to screen for antibodies that specifically bind to key proteins. It also allowed scientists to identify exactly which proteins key antibodies recognize. This was especially useful for scientists working with monoclonal antibodies, artificially produced antibodies that are carbon copies of each other.
Winter found a way to turn the tables on the process: He used the technique developed by Smith to make phages display key pieces of antibodies on their surface. This was a huge breakthrough because it allowed scientists to directly screen for genes that make antibodies to almost any protein. (Traditionally, scientists produced antibodies by injecting proteins into experimental animals and then purifying the antibodies from the animals’ blood. But that produces a mix of different antibodies, some of which bind more tightly than others to a given protein.)
Winter’s technique has allowed researchers to produce, for example, a very specific human antibody to a protein called TNF-α, which plays a role in several autoimmune diseases. The antibody, called adalimumab, is used to treat rheumatoid arthritis, psoriasis, and inflammatory bowel disease.
“I didn’t have any idea [the technique] would be so commercially successful,” Winter said at a press conference in Cambridge today. “In the 1990s, the pharmaceutical industry was run by chemists. To them, a drug was a chemical. They didn’t believe antibodies would be therapeutics.” The field is still advancing rapidly, he added; his own team is now studying smaller antibody mimics based around peptides, called bicycles. “They have different pharmacological properties from antibodies. But they can permeate deep into tissues and cancers,” Winter said.
The award “wonderfully recognizes the power of harnessing protein evolution to solve a wide range of problems in the molecular sciences,” says David Liu, a chemist and directed evolution expert at Harvard University. “My hat’s off to Smith, Winter, and Arnold for their contributions to this multidisciplinary field that beautifully integrates chemistry, molecular biology, and protein science.”
“At first glance, it may seem that the chemistry Nobel has been ‘biologised’ again. It is sometimes hard to see how an enzyme, or a phage, are ‘chemistry’—but they are!” Oliver Jones, a chemist at RMIT University in Melbourne, Australia, said in a statement distributed by the United Kingdom’s Science Media Center. “Chemistry underpins so many things in our lives, even if it is not always immediately obvious and it is great that these discoveries are getting recognised.”
Arnold was scheduled to give a lecture at a Texas university this morning when she got the Nobel call. Science reached her at an airport where she was catching a flight back to California, after the school graciously canceled the talk. "I’m going to go home and see my children. And I’m going to go over to Caltech and party with my students."
Winter said he had “absolutely no inkling” that he might win a Nobel, despite having been nominated in the past. When he got the call from Stockholm this morning, “I was recovering from a college feast so I had had some aspirin and had a coffee,” he said. “Hence I was a bit numb and thought, ‘Is this real?’” The next feast will be later today at LMB: “They’ve already told me the champagne bill will be £2793 and could they have my credit card number.”
With reporting by Robert F. Service, Lila Guterman, and Daniel Clery.