Use of Evolution to Design Molecules Nets Nobel Prize in Chemistry for 3 Scientists

Use of Evolution to Design Molecules Nets Nobel Prize in Chemistry for 3 Scientists

Three scientists shared this year’s Nobel Prize in Chemistry for tapping the power of evolutionary biology to design molecules with a range of practical uses.

Those include new drugs, more efficient and less toxic reactions in the manufacture of chemicals and plant-derived fuels to replace oil, gas and coal extracted from the ground.

Half of the prize and the accompanying $1 million, announced on Wednesday in Stockholm, went to Frances H. Arnold, a professor of chemical engineering at the California Institute of Technology. She is only the fifth woman to win a chemistry Nobel and the first since 2009.

[Read more about Dr. Arnold’s scientific career.]

The other half of the prize is shared by George P. Smith, an emeritus professor of biological sciences at the University of Missouri, and Gregory P. Winter, a biochemist at the M.R.C. Laboratory of Molecular Biology in England.

The prize highlights the narrowing of the gap between biology and some fields of chemistry as chemists turn to nature for inspiration.

“I always wanted to be a protein engineer,” Dr. Arnold said in an interview. “Proteins are marvelous molecular machines, tremendously complex but responsible for all the functions of life. I wanted to be an engineer of the biological world.”

At first, Dr. Arnold attempted “rational design,” employing logic and knowledge of how proteins function to try to build new enzymes — proteins that act as catalysts for chemical reactions. But enzymes are large, complicated molecules — some consisting of thousands of amino acids — and it is hard to figure out how a shift in one twist of the molecule affects how it works.

In desperation, she said, she turned to evolution.

“I copied nature’s inventions, this wonderful process of evolution, to breed molecules like you breed cats and dogs,” she said.

For this “directed evolution” research, she inserted the gene that produced the enzyme she wanted to study into fast-reproducing bacteria. With mutations of the gene, she could then examine how well variations of the enzyme worked. She chose the one that worked best and repeated the process — just like evolution chooses the survival of the fittest over succeeding generations.

“There was still a lot of criticism at that point as to whether it was science,” said Christopher Voigt, a professor of bioengineering at Massachusetts Institute of Technology and editor-in-chief of the American Chemical Society’s Synthetic Biology journal. He was also a graduate student of Dr. Arnold’s two decades ago.

In her initial experiments in the 1990s, she was able to produce an enzyme more than 200 times as effective as the one she started with by the third generation.

The next innovation, as highlighted in materials supplied by the Royal Swedish Academy of Sciences, came from Willem P.C. Stemmer, a Dutch researcher who came up with a way to generate a wider assortment of enzyme variants more quickly.

The technique, called DNA shuffling, cut apart different versions of a gene and mixed pieces into a new variant — sort of the molecular equivalent of the genetic mixing in the offspring of two animals. (Nobels are only awarded to living scientists; Dr. Stemmer died in 2013.)

These techniques have led to stain-removing enzymes in laundry detergents and promising advances in the production of biofuels.

Dr. Arnold, who has been honored with a multitude of awards for her research, was not expecting a Nobel. She was asleep in a hotel room in Dallas, where she was scheduled to give a lecture. The ringing of her cell phone woke her.

“I always first think, it’s ‘One of my family members needs something,’” she said. “I saw the telephone number, and I recognized Europe. I said, oh my goodness, so somebody in Europe needs something.”

It was someone calling from Stockholm saying she had won a Nobel. “At which point my mouth dropped and I’m speechless,” she said. “Which is rare.”

She canceled the lecture — “I’m going to be a bad guest,” she said — and flew back to California fora news conference at Caltech about her Nobel.

Dr. Smith and Dr. Winter were honored for another corner of synthetic biology, a field that emerged in the 1980s after technique called polymerase chain reaction enabled prolific duplication of DNA. In their work, harnessed the power of bacteriophages — viruses that infect bacteria — for applications that eventually contributed to novel drugs that treat a range of diseases.

Dr. Smith was looking to identify unknown genes that were the blueprints for the production of known peptides — short pieces of protein.

Bacteriophages, which consist of a piece of DNA within a capsule of proteins, proved handy tools. He embedded a variety of candidate genes within the phages’ DNA. The phages then added those proteins to their outer coating.

An antibody is like a key that fits into a specific protein lock. The body’s immune system uses antibodies to identify invading pathogens.

When certain phages succeeded in attaching to a known antibody, the scientists could then make the connection between the peptide and the gene that produced it.

The academy described this approach, known as phage display, as “brilliant in its simplicity.”

Dr. Smith deferred credit to the other laureates, especially Dr. Winter. “They won the Nobel prize for me and they got it themselves as well,” Dr. Smith said during a news conference.

He said the others had found ways to apply technology he developed for subsequent advances.

“I was not smart enough to anticipate what would come out of this research,” Dr. Smith said. “I had a much narrower view than I have now.”

Dr. Winter built on Dr. Smith’s work and used phage display to develop antibodies that could serve as new treatments for diseases like multiple sclerosis and cancer. Traditional drugs use small molecules to alter processes within cells. The development of antibodies was outside the expertise of major drug companies.

“In the early 90s, people didn’t believe antibodies could be therapeutics,” Dr. Winter said during a telephone news conference on Wednesday.

Dr. Winter inserted the gene for producing an antibody into the phages and then examined variants of the antibodies, selecting the ones that bound most effectively to the desired targets. Repeated evolution of the gene led to more effective antibodies.

The first antibody drug developed this way, adalimumab, which is sold under the brand name Humira, was approved in 2002 to treat rheumatoid arthritis, psoriasis and inflammatory bowel diseases.

Other antibodies are used to kill cancer cells, neutralize anthrax and slow the progress of lupus, an autoimmune disease. Additional antibodies are in testing to treat diseases like Alzheimer’s.

Dr. Winter said he was at his office when his phone rang: “They said, ‘We have a very important announcement for you. Am I speaking to Dr. Winter?’ And I said, ‘Well, well, yes.’ They said, ‘Hold the line.’ And then the line went dead.”

And a short while, the phone rang again with the news of the Nobel.

“It came as a little bit of a shock,” he said, “and I felt a bit numb for a while wondering whether this is real.”

Dr. Winter said earlier in his career, before his work using bacteriophages for developing antibody medicines, he pursued basic scientific understandings of evolution — science for the sake of science.

He succeeded in tweaking a mouse antibody to work inside humans. It was then tested as a treatment for a woman with cancer.

“We didn’t know what would happen, I was actually rather worried that this antibody might be rather ferocious and she might drop dead,” Dr. Winter said.

After a few days, the tumor started shrinking, and he went to visit the patient. “I went in there and this lovely lady, who was knitting quite calmly,” he said.

“She asked me what I was feeling about this,” he said. “I said I’m frankly delighted that you haven’t dropped dead.”

The woman found Dr. Winter’s candor refreshing compared with the more cautious words from her doctors. She said she would happy if the experimental treatment only extended her life a few months because her husband was dying, and she wanted to be with him.

That experience made a lasting impression.

“What it put on me is a moral imperative on actually making sure that I was producing could be used for the public benefit,” he said.

Jacques Dubochet, Joachim Frank and Richard Henderson were recognized for developing a new way to assemble precise three-dimensional images of biological molecules like proteins, DNA and RNA. Their work has helped scientists decipher processes within cells that were previously invisible, and has led to better understanding of viruses like Zika.

• Arthur Ashkin of the United States, Gérard Mourou of France and Donna Strickland of Canada were awarded the Nobel Prize in Physics on Tuesday for their work developing tools made of light beams.

• James P. Allison and Tasuku Honjo were awarded the Nobel Prize in Physiology or Medicine on Monday for a discovery that the body’s immune system can be used to attack cancer cells.

• The Nobel Peace Prize will be announced on Friday in Norway. Read about last year’s winner, the International Campaign to Abolish Nuclear Weapons.

• The Nobel Memorial Prize in Economic Science will be announced on Monday in Sweden. Read about last year’s winner, Richard H. Thaler.

The Nobel Prize in Literature has been postponed. The institution that chooses the laureate is embroiled in a scandal involving allegations of sexual misconduct, financial malpractice and repeated leaks — a crisis that led to the departure of several board members and required the intervention of the king of Sweden. Read about last year’s winner, Kazuo Ishiguro.

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Using Evolution to Design a Diverse Array of Useful Molecules
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