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Biological Chemistry

Frances H. Arnold, George P. Smith, and Gregory P. Winter share 2018 Nobel Prize in Chemistry

Trio recognized for harnessing evolution to identify new enzymes and binding proteins

by Celia Henry Arnaud
October 3, 2018

 

LN-chemnobels.jpg
Credit: Caltech; University of Missouri; and MRC Laboratory of Molecular Biology
Arnold, Smith, and Winter.

The 2018 Nobel Prize in Chemistry was awarded to Frances H. Arnold of California Institute of Technology for the directed evolution of enzymes and to George P. Smith of the University of Missouri and Gregory P. Winter of the MRC Laboratory of Molecular Biology for the phage display of peptides and antibodies. Arnold will receive half of the approximately $1 million prize; Smith and Winter will split the other half equally.

This year’s prize “recognizes the power of harnessing protein evolution to solve a wide range of problems in the molecular sciences,” says David R. Liu of Harvard University, who has developed a version of directed evolution called phage-assisted continuous evolution. “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.”  

Credit: C&EN/ACS Productions
For a look at the research that earned the laureates a coveted call from Sweden, watch our newest episode of Speaking of Chemistry.
CORRECTION: At about 2:30 in the video, Gregory Winter is erroneously referred to as George Winter.

Directed evolution is an iterative lab method involving mutation and screening that speeds up the natural selection process through which life on Earth evolved. In Arnold’s technique, she introduces random mutations into the gene for a starting enzyme, expresses the variant genes in bacteria, and screens the mutated enzymes produced by the microbes for desired activity. By repeating this process with the best performers, researchers can find proteins with the desired enzymatic properties in terms of activity, binding affinity, or specificity.

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Credit: Science
Through directed evolution, researchers changed 12 amino acids (red circles) in this enzyme to yield a protein that could oxidize alkenes in a unique way (Science 2017, DOI: 10.1126/science.aao1482).

Arnold conducted the first directed evolution of enzymes in 1993. In that work, she evolved a version of the enzyme subtilisin E that was active at high concentrations of the polar organic solvent dimethylformamide. Four rounds of mutagenesis and screening resulted in an enzyme that was 256 times as active as the original enzyme.

Smith reported the original phage display method in 1985. In this library-based method for screening for proteins that bind a specific molecule, the gene for each member of the library is inserted in the DNA for coat protein III of phage, a virus that infects bacteria. The phage infects and reproduces in bacteria. Scientists can then use the target molecule as bait to enrich phages released by the bacteria that have the binding protein of interest on their surface.

Sequencing the genetic material of the collected phages yields genes for proteins with desired binding affinity.

Winter extended phage display to screening for novel antibodies. In 1990, Winter’s team reported the phage display of a folded and fully functional antibody fragment called a single-chain variable fragment. This first demonstration identified selective antibodies that could bind hen egg-white lysozyme but not human lysozyme or turkey egg-white lysozyme.

Directed evolution and phage display have both become widely used methods. C&EN featured Provivi, a company founded by Arnold and two of her coworkers, in its 10 Start-ups to Watch in 2015. Provivi uses enzymes developed through directed evolution to make insect pheromones for pest control. And researchers have used phage display to identify antibodies with high binding affinity for use as pharmaceuticals. The first approved drug developed using phage display is Abbvie’s Humira (adalimumab), which was approved by the U.S. Food & Drug Administration in 2002.

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“This is a fantastic award that recognizes how laboratory evolution, in a few short decades, has revolutionized our ability to tailor the properties of biomolecules for applications unimagined in nature,” says Donald Hilvert, an expert in directed evolution at the Swiss Federal Institute of Technology, Zurich.

Commenting on the biological flavor of this year’s chemistry Nobel, Peter K. Dorhout, president of the American Chemical Society, says, “This is chemistry. Chemistry is broad and deep. In the case of evolved enzymes, it’s catalytic chemistry and organic chemistry. To develop and understand the critical tools to evaluate how cells behave is also fundamental analytical chemistry.”

UPDATE: This story was updated on Oct. 8, 2018, to correct the method that David R. Liu developed. It's phage-assisted continuous evolution, not phage-assisted directed evolution.

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Comments
William Rubin (October 3, 2018 11:03 AM)
"Directed evolution is an iterative lab method involving mutation and screening that speeds up the natural selection process through which life on Earth evolved."

There's no such thing as directed evolution. It's an oxymoron. It's called creation. Stop perpetuating ignorance with propaganda. Life adapts, it does not evolve, there's a huge difference. There is random mutation and the naturally-occurring reconfiguration of DNA via offspring, etc. but they have never given rise to new species. If people understood biology and biochemistry, they wouldn't follow such nonsense. Life on earth was created, it didn't evolve.
Gerald Streit (October 3, 2018 3:12 PM)
Correct! Evolution, by definition, is unguided and unpurposed. The process was directed, yes. Laboratory conditions and temperatures, purity of reagents, purity of solvents, purposeful selection of certain products....these were all actions or products of intelligence. Bears no resemblance to evolution.
Cliff Burford (October 27, 2018 6:41 AM)
If genetic engineering of fruits flies is not directed evolution, I don't know what is.
And how about non-reproductive mosquitoes that reduce the populations of
mosquitoes which spread of diseases.

Please take your misinformed trolling to a non-scientific website,
where GOP thugs and their kind don't know any better.

Don't bother trying to send me letter bombs, I live outside the US,
where the post office is much more vigilant

Sameen Ahmed Khan (October 3, 2018 12:19 PM)
Heartiest Congratulations!!! From Sameen Ahmed KHAN, College of Arts and Applied Sciences, Dhofar University, Salalah, Sultanate of OMAN.
Sameen Ahmed Khan (October 3, 2018 2:04 PM)
Gregory Paul Winter was the recipient of the "1995 King Faisal International Prize for Medicine"

Sameen Ahmed KHAN
Dhofar University
Salalah
Sultanate of OMAN
Kamal Ibrahim Aly (October 3, 2018 2:55 PM)
Congratulation for all.
Kamal I Aly,
Professor, Assiut University
EGYPT

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