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Frances Arnold

Directed Evolution of Enzymes

Patent No. 6,153,410

Frances Arnold is a pioneer of directed evolution, a process for “breeding” scientifically interesting or technologically useful proteins by mutating and recombining their DNA sequences and screening for desired properties.

Arnold’s methods accelerate the evolution of proteins, especially enzyme catalysts, for a wide range of applications including developing new biological routes to making pharmaceuticals, industrial chemicals, consumer chemicals, and biofuels. Enzymes evolved in the laboratory have capabilities beyond those found in nature. Arnold’s research has led to practical applications as varied as creating laundry detergents and new drug development, and her methods are now used in hundreds of labs around the world.

A graduate of Princeton and the University of California, Berkeley, Arnold co-founded biofuel company Gevo in 2005. On the faculty of Caltech, her main focus is renewable energy and sustainable chemistry.  She is one of only a few individuals to be elected to all three National Academies, and her many additional honors include the Draper Prize and the National Medal of Technology and Innovation.

Arnold, F. The Library of Maynard-Smith: My Search for Meaning in the Protein Universe. Microbe, ASM News, 6, 316-318.

Arnold Wins Draper Prize. (2011, Jan. 4), retrieved April 24, 2014 from California Institute of Technology Website:

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Romero, P., & Arnold, F. Exploring Protein Fitness Landscapes by Directed Evolution. Nat. Rev. Mol. Cell Biology , 10, 866-876.

Roosevelt, Margot. (2011, Jan. 30). Caltech’s Frances Arnold wins Draper Prize for biofuels-related research, retrieved April 24, 2014 from Lost Angeles Times Online:

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The daughter of a nuclear physicist, Arnold grew up in Pittsburgh, Pennsylvania. Her father, William Howard Arnold – an expert in nuclear power, nuclear fuel, and nuclear waste disposal – was elected to the National Academy of Engineering in 1974 at the age of 43. Arnold has said she didn’t know one day she would become a scientist, yet she herself was elected to the NAE at 43. Arnold told Slate in 2013 that when she was younger, she envisioned herself as a diplomat or the CEO of a multinational corporation.

She graduated from Princeton University in 1979, where she studied mechanical and aerospace engineering. Her interest in alternative energy developed during the 1970s oil crisis and when concerns over the safety of nuclear energy appeared. After graduation, Arnold worked for the Solar Energy Research Institute (SERI), currently the National Renewable Energy Laboratory.  She wrote position papers, designed solar energy facilities for remote locations, and worked in the field, including in South Korea.

With national interest in renewable energy waning with a change in administration, Arnold left SERI at the end of 1980 to attend the University of California-Berkeley, where she switched fields to biochemical engineering and the brand-new industry that was being built based on advances in molecular biology and genetic engineering. She received her Ph.D. in Chemical Engineering in 1985 and stayed for a year longer to study biophysical chemistry as a postdoctoral researcher. Arnold continued postdoctoral work at Caltech and in 1987 was appointed assistant professor of chemical engineering.

At Caltech, Arnold focused her research on “protein engineering”, developing proteins for use in the medical, chemical, and energy industries. Since no one really knew how to design useful proteins, she conducted “cheap” and “fast” experiments to efficiently find things that did work.  She accumulated changes to the protein in an evolutionary approach that was not appreciated by some of her colleagues, who felt that protein engineering was best done based on deep understanding. In the 1990s, using her unorthodox engineering methods, Arnold pioneered directed evolution of proteins.

Directed evolution is used around the globe to guide the creation of proteins and genetically engineered organisms with desirable properties and new capabilities. It enables solutions in a wide range of chemical engineering, bioengineering, and biochemical areas of research, including food chemistry, pharmaceuticals, toxicology, industrial chemical manufacturing, gene delivery systems, consumer chemicals, and biofuels.

By randomly mutating the gene encoding a specific protein and screening for desired functions, Arnold was able to direct its evolution towards specific goals. The method mimics Darwinian evolution in the lab under an extremely accelerated timescale.  With directed evolution, however, the human experimenter decides the selection of the “fittest”.  Thus directed evolution is like breeding, but at the molecular level.

Today, researchers still cannot design DNA sequences to meet precise specifications or guide an organism to perform desired functions and that is where Arnold’s methods come in. Using directed evolution, researchers can produce new proteins with different and more desirable traits than the protein offered prior to the manipulation. Researchers mutate a protein, select the best mutations, and then repeat the process. Each repetition manipulates the protein into displaying the properties needed for a specific use. By causing mutations and testing them, her process speeds up and guides evolution along a particular path.

In 1999, Arnold turned her focus back to the challenges of renewable and alternative energy. She hopes that she will be able to solve some of the biggest problems in finding replacements for and improvements to fossil fuels with the directed evolution of protein catalysts called enzymes. Currently, she oversees 20 students and post-doctoral researchers in her Caltech lab in a quest to find uses for reengineered enzymes and proteins.

Arnold’s directed evolution research earned her the 2011 National Medal of Technology and Innovation and the 2011 Charles Stark Draper Prize from the National Academy of Engineering, an award often described as the Nobel Prize for engineering. She was the first female researcher to receive the Draper prize. She is also one of two women elected to all three American National Academies – the National Academy of Science, the National Academy of Engineering and the National Academy (we just changed the name!) of Medicine. Arnold has also worked with the Science & Entertainment Exchange (The Exchange), a program of the National Academy of Science that is a resource for Hollywood screenwriters to show science in a realistic way on the big screen.

Listed as the co-inventor on more than 30 U.S. patents, Arnold served as science advisor for over 10 companies, which include Maxygen, Amryis, Codexis, Mascoma, Fluidgm, and Genomatica. In 2005, she co-founded the biofuels company, Gevo Inc., where she also served as a science advisor.

Recently she has been working on proteins that would bind to neurotransmitters so these can be detected by MRIs. Currently, MRIs are only capable of showing changes in blood flow, which is not always a perfect translation to what is happening in the brain. She has also been evolving proteins that respond to light and activate neurons or report on neural activation for optogenetics research. Her new tools could help researchers understand and control behavior in living animals and develop better drugs to treat Alzheimer’s, Parkinson’s, and depression.

Arnold, a breast cancer survivor, has three sons.  She lives in La Cañada Flintridge in California, and her hobbies include scuba diving, traveling, skiing, dirt-bike riding, and hiking.

B.S. Mechanical and Aerospace Engineering, Princeton University, 1979
Ph.D. Chemical Engineering, UC Berkeley, 1985
Postdoctoral, UC Berkeley, Biophysical Chemistry, 1985
Postdoctoral, Caltech, Chemistry, 1986

Arnold is best known as a pioneer of the directed evolution of enzymes – a protein engineering method that mimics the process of natural selection but is much faster. The process reshuffles the deck of a protein’s sequence to produce hundreds of new enzyme variations before testing them to verify if they can produce a desired outcome. When the process is repeated to accumulate beneficial mutations, the method allows researchers to optimize protein molecules for specific tasks.

“I meet so many young people who want to plan out their lives and want a recipe. They want me to tell them how to succeed. I didn’t follow a recipe. I followed my instincts. I was lucky to be passionate about a field that was full of opportunity. Most innovative things are not obvious to other people at the time. You have to believe in yourself. If you’ve got a good idea, follow it even though others tell you it’s not.” – As told to LA Times in 2011

“The code of life is like a Beethoven symphony. We have not yet learned how to write music like that. But evolution does it very well. I am learning how to use evolution to compose new music.” – As told to the LA Times in 2011

“Biology is a master in using resources intelligently.” – Chemistry Review

Twitter @francesarnold

Patent Number

Directed Evolution Of Oxidase Enzymes
Petrounia; Ioanna P.
Sun; Lianhong
*Listed for principal patent(s).
Immobilized Metal Aqueous Two-Phase Extraction And Precipitation
Composition Of Matter Comprising An Imprinted Matrix Exhibiting Selective Binding Interactions Through Chelated Metals
Subtilisin Variants Suitable For Hydrolysis And Synthesis In Organic Media
Lipid-Based Metal Sensor
Para-Nitrobenzyl Esterases With Enhanced Activity In Aqueous And Nonaqueous Media
Adsorbents For Amino Acid And Peptide Separation
Metal Chelating Lipids Which Are Useful As Sensors In Fluorometric Methods For The Detection Of Metal Ions
Para-Nitrobenzyl Esterases With Enhanced Activity In Aqueous And Nonaqueous Media
Thermally Stable Para-Nitrobenzyl Esterases
Sensors For Sugars And Other Metal Binding Analytes
Recombination Of Polynucleotide Sequences Using Random Or Defined Primers
Recombination Of Polynucleotide Sequences Using Random Or Defined Primers
ECB Deacylase Mutants
Hydantoinase Variants With Improved Properties And Their Use For The Production Of Amino Acids
Method For Creating Polynucleotide And Polypeptide Sequences
Microfabricated Cell Sorter For Chemical And Biological Materials
Oxygenase Enzymes And Screening Method
Directed Evolution Of Galactose Oxidase Enzymes
Method For Creating Polynucleotide And Polypeptide Sequences
Microfabricated Cell Sorter
Glucose 6-Oxidases
Cytochrome P450 Oxygenases
Thermostable Peroxide-Driven Cytochrome P450 Oxygenase Variants And Methods Of Use
Peroxide-Driven Cytochrome P450 Oxygenase Variants
Regio- And Enantioselective Alkane Hydroxylation With Modified Cytochrome P450
Cytochrome P450 Oxygenases
Peroxide-Driven Cytochrome P450 Oxygenase Variants
Method For Creating Polynucleotide And Polypeptide Sequences
Regio- And Enantioselective Alkane Hydroxylation With Modified Cytochrome P450
Methods And Systems For Selective Fluorination Of Organic Molecules
Cytochrome P450 Oxygenases
Engineered Microorganisms Capable Of Producing Target Compounds Under Anaerobic Conditions
Methods And Systems For Selective Fluorination Of Organic Molecules
Regioselective Alkane Hydroxylation With A Mutant Alkb Enzyme
Regio- And Enantioselective Alkane Hydroxylation With Modified Cytochrome P450
Regioselective Alkane Hydroxylation With A Mutant Cyp153a6 Enzyme
Cytochrome P450 Oxygenases

Occupation: Dick and Barbara Dickinson Professor of Chemical Engineering and Biochemistry at the California Institute of Technology (Caltech). She is also the co-founder of Gevo Inc.

Born: July 25, 1956, Pittsburgh, PA

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