Frances Arnold

Frances Arnold
Born Frances Hamilton Arnold
(1956-07-25) July 25, 1956[1]
Edgewood, Pennsylvania, U.S.
Education Princeton University (BS)
University of California, Berkeley (MS, PhD)
Known for Directed evolution of enzymes
Awards Garvan–Olin Medal (2005)
FASEB Excellence in Science Award (2007)
Draper Prize (2011)
National Medal of Technology and Innovation (2013)
Sackler Prize in Convergence Research (2017)
Nobel Prize in Chemistry (2018)
Scientific career
Fields Chemical engineering
Bioengineering
Biochemistry
Institutions California Institute of Technology
Thesis Design and Scale-Up of Affinity Separations (1985)
Doctoral advisor Harvey Blanch
Doctoral students Christopher Voigt
Huimin Zhao

Frances Hamilton Arnold (born July 25, 1956)[1] is an American chemical engineer and Nobel Laureate. She is the Linus Pauling Professor of Chemical Engineering, Bioengineering and Biochemistry at the California Institute of Technology (Caltech). In 2018, she was awarded Nobel Prize in Chemistry for pioneering the use of directed evolution to engineer enzymes.

Early life and education

Arnold is the daughter of Josephine Inman (née Routheau) and nuclear physicist William Howard Arnold, and the granddaughter of Lieutenant General William Howard Arnold.[2] She grew up in Pittsburgh suburb Edgewood, and Pittsburgh neighborhoods of Shadyside and Squirrel Hill, graduating from the city's Taylor Allderdice High School in 1974.[3] As a high schooler, she hitchhiked to Washington, D.C. to protest the Vietnam War and lived on her own working as a cocktail waitress at a local jazz club and a cab driver.[4]

Arnold graduated in 1979 with a B.S. degree in mechanical and aerospace engineering from Princeton University, where she focused on solar energy research.[5] In addition to the courses required for her major, she took classes in economics, Russian, and Italian, and envisioned herself as becoming a diplomat or CEO, even considering getting an advance degree in international affairs.[6] She took a year off from Princeton after her second year to travel to Italy and work in a factory that made nuclear reactor parts, then returned to finish out her studies.[7] Back at Princeton, she began studying with Princeton's Center for Energy and Environmental Studies – a group of scientists and engineers, at the time led by Robert Socolow, working to develop sustainable energy sources, a topic that would become a key focus of Arnold's later work.[7]

After graduating from Princeton in 1979, Arnold worked as an engineer in South Korea and Brazil and at Colorado's Solar Energy Research Institute.[7] At the Solar Energy Research Institute (now the National Renewable Energy Laboratory), she worked on designing solar energy facilities for remote locations and helped write United Nations (UN) position papers.[6]

She then enrolled at the University of California, Berkeley, where she earned Ph.D. degree in chemical engineering in 1985[8] and became deeply interested in biochemistry in the process.[9][7] Her thesis work, carried out in the lab of Harvey Warren Blanch, investigated affinity chromatography techniques.[8][10]

Career

After earning her Ph.D., Arnold completed postdoctoral research in biophysical chemistry at Berkeley.[11] In 1986, she joined the California Institute of Technology as a visiting associate. She was promoted to assistant professor in 1986, associate professor in 1992, and full professor in 1996. She was named the Dick and Barbara Dickinson Professor of Chemical Engineering, Bioengineering and Biochemistry in 2000 and, her current position, the Linus Pauling Professor of Chemical Engineering, Bioengineering and Biochemistry in 2017.[12] In 2013, she was appointed director of Caltech's Donna and Benjamin M. Rosen Bioengineering Center.[12]

Arnold is a member of the Advisory Board of the Joint BioEnergy Institute and the Packard Fellowships in Science and Engineering, and she serves on the President's Advisory Council of the King Abdullah University of Science and Technology (KAUST). She is currently serving as a judge for The Queen Elizabeth Prize for Engineering. She worked with the National Academy of Science's Science & Entertainment Exchange to help Hollywood screenwriters accurately portray science topics.[13]

She is co-inventor on over 40 US patents.[9] She co-founded Gevo, Inc., a company to make fuels and chemicals from renewable resources in 2005.[9] In 2013, she and two of her former students, Peter Meinhold and Pedro Coelho, cofounded a company called Provivi to research alternatives to pesticides for crop protection.[9][14] She has been on the corporate board of the genomics company Illumina Inc. since 2016.[15][16]

Research

Arnold is credited with pioneering the use of directed evolution to create enzymes (biochemical molecules—often proteins—that catalyze, or speed up, chemical reactions) with improved and/or novel functions.[17] The directed evolution strategy involves iterative rounds of randomly mutating proteins' genes and screening for proteins with improved functions and it has been used to create useful biological systems, including enzymes, metabolic pathways, genetic regulatory circuits, and organisms. In nature, evolution by natural selection can lead to proteins (including enzymes) well-suited to carry out biological tasks, but natural selection can only act on existing sequence variations (mutations) and typically occurs over long time periods.[18] Arnold speeds up the process by introducing mutations in the underlying sequences of proteins; she then tests these mutations' effects. If a mutation improves the proteins' function she can keep iterating the process to optimize it further. This strategy has broad implications because it can be used to design proteins for a wide variety of applications.[19] For example, she has used directed evolution to design enzymes that can be used to produce renewable fuels and pharmaceutical compounds with less harm to the environment.[17]

One advantage of directed evolution is that the mutations do not have to be completely random; instead they can be random enough to discover unexplored potential, but not so random as to be inefficient. The number of possible mutation combinations is astronomical, but instead of just randomly trying to test as many as possible, Arnold integrates her knowledge of biochemistry to narrow down the options, focusing on introducing mutations in areas of the protein that are likely to have the most positive effect on activity and avoiding areas in which mutations would likely be, at best, neutral and at worst, detrimental (such as disrupting proper protein folding).[17]

Arnold applied directed evolution to the optimization of enzymes (although not the first person to do so, see e.g. Barry Hall[20]). In[17] her seminal work, published in 1993, she used the method to engineer a version of subtilisin E that was active in a highly unnatural environment, namely in the organic solvent DMF.[21] She carried out the work using four sequential rounds of mutagenesis of the enzyme's gene, expressed by bacteria, through error-prone PCR. After each round she screened the enzymes for their ability to hydrolyze the milk protein casein in the presence of DMF by growing the bacteria on agar plates containing casein and DMF. The bacteria secreted the enzyme and, if it were functional, it would hydrolyze the casein and produce a visible halo. She selected the bacteria that had the biggest halos and isolated their DNA for further rounds of mutagenesis.[17] Using this method, she designed an enzyme that had 256 times more activity in DMF than the original.[22]

Following her seminal work, Arnold has further developed her methods and applied them under different selection criteria in order to optimize enzymes for different functions. She showed that, whereas naturally evolved enzymes tend to function well at a narrow temperature range, enzymes could be produced using directed evolution that could function at both high and low temperatures.[17] In addition to improving the existing functions of natural enzymes, Arnold has designed enzymes that perform functions for which no previous specific enzyme existed, such as when she evolved cytochrome P450 to carry out cyclopropanation[23] and carbene and nitrene transfer reactions.[17][24]

In addition to evolving individual molecules, Arnold has used directed evolution to co-evolve enzymes in biosynthetic pathways, such as those involved in the production of carotenoids[25] and L-methionine[26] in Escherichia coli (which has the potential to be used as a whole-cell biocatalyst).[17]

Arnold has applied these methods to biofuel production. For example, she evolved bacteria to produce the biofuel isobutanol; it can be produced in E. coli bacteria, but the production pathway requires the cofactor NADPH, whereas E. coli makes the cofactor NADH. To circumvent this problem, Arnold evolved the enzymes in the pathway to use NADH instead of NADPH, allowing for the production of isobutanol.[17][27]

Arnold has also used directed evolution to design highly specific and efficient enzymes that can be used as environmentally-friendly alternatives to some industrial chemical synthesis procedures.[17] She, and others using her methods, have engineered enzymes that can carry out synthesis reactions more quickly, with fewer by-products, and in some cases eliminating the need for hazardous heavy metals.[22] The method has been adopted by some groups in pharmacology. For example, one of Arnold's former students, Jeffrey Moore, and colleagues used directed evolution to evolve an enzyme to produce the diabetes drug sitagliptin (Januvia).[14]

Arnold also uses structure-guided protein recombination to combine parts of different proteins to form protein chimeras with unique functions. She developed computational methods, such as SCHEMA, to predict how the parts can be combined without disrupting their parental structure, so that the chimeras will fold properly, and then applies directed evolution to further mutate the chimeras to optimize their functions.[28][29]

At Caltech, Arnold runs a laboratory that continues to study directed evolution and its applications in environmentally-friendly chemical synthesis and green/alternative energy, including the development of highly active enzymes (cellulolytic and biosynthetic enzymes) and microorganisms to convert renewable biomass to fuels and chemicals.

Personal life

Arnold lives in La Cañada Flintridge, California. She was married to James E. Bailey and they had one son, James. Bailey died of cancer in 2001.[30][15] She later married Caltech astrophysicist Andrew E. Lange and they had two sons, William and Joseph.[31][32] Lange took his own life in 2010 and one of their sons, William Lange-Arnold, died in an accident in 2016.[15] Arnold was diagnosed with breast cancer in 2005 and underwent treatment for 18 months.[33][34] Her hobbies include traveling, scuba diving, skiing, dirt-bike riding and hiking.[34]

Honors and awards

Arnold's work has been recognized by many awards, including the 2018 Nobel Prize in Chemistry, the 2011 National Academy of Engineering (NAE) Draper Prize (the first woman to receive it), and a 2011 National Medal of Technology and Innovation.[12] She was elected to the American Academy of Arts and Sciences in 2011 and inducted into the National Inventors Hall of Fame in 2014.[12] She was the first woman to be elected to all three National Academies in the United States – the National Academy of Engineering (2000), the National Academy of Medicine, formerly called the Institute of Medicine (2004), and the National Academy of Sciences (2008).[12]

Arnold is a Fellow of the American Association for the Advancement of Science, the American Academy of Arts and Sciences, the American Academy of Microbiology, the American Institute for Medical and Biological Engineering and an International Fellow of the UK's Royal Academy of Engineering in 2018.[35][36]

In 2016 she became the first woman to win the Millennium Technology Prize, which she won for pioneering directed evolution.[37] In 2017, Arnold was awarded the Raymond and Beverly Sackler Prize in Convergence Research by the National Academy of Sciences, which recognizes extraordinary contributions to convergence research.[38]

In 2018 she was awarded the Nobel Prize in Chemistry for her work in directed evolution, making her the fifth woman to receive the award in its 117 years of existence, and the first American woman.[39][40] She received a one-half share of the award, with the other half jointly awarded to George Smith and Gregory Winter "for the phage display of peptides and antibodies."[17] She is the first female graduate of Princeton to win a Nobel Prize and the first person who got their undergraduate degree from Princeton (male or female) to receive a Nobel Prize in one of the natural sciences categories (chemistry, physics, and physiology of medicine).[5]

References

  1. 1 2 "Francis H. Arnold – Facts – 2018". NobelPrize.org. Nobel Media AB. 3 October 2018. Retrieved 5 October 2018.
  2. ↑ Memorial Tributes. National Academies Press. September 26, 2017. doi:10.17226/24773. ISBN 978-0-309-45928-0.
  3. ↑ Guarino, Ben (October 3, 2018). "'Her work is incredible': Pittsburgh native Frances Arnold shares Nobel Prize in chemistry". Pittsburgh Post-Gazette.
  4. ↑ Kharif, Olga (March 15, 2012). "Frances Arnold's Directed Evolution". Bloomberg Businessweek. Retrieved September 1, 2012.
  5. 1 2 "Princeton engineering alumna Frances Arnold wins Nobel Prize in Chemistry". Princeton University. Retrieved 2018-10-04.
  6. 1 2 Ouellette, Jennifer (2013-03-08). "The Director of Evolution". Slate. ISSN 1091-2339. Retrieved 2018-10-05.
  7. 1 2 3 4 "Evolution Gets an Assist". Princeton Alumni Weekly. 2014-10-17. Retrieved 2018-10-05.
  8. 1 2 Arnold, Frances Hamilton (1985). Design and Scale-Up of Affinity Separations) (PhD). University of California, Berkeley. OCLC 910485566 – via ProQuest. (Subscription required (help)).
  9. 1 2 3 4 "Frances H. Arnold". NAE Website. Retrieved 2018-10-03.
  10. ↑ "A to G | Harvey W. Blanch". stage.cchem.berkeley.edu. Retrieved 2018-10-03.
  11. ↑ "Interview with Frances H. Arnold – Design by Evolution". www.chemistryviews.org. Retrieved October 3, 2018.
  12. 1 2 3 4 5 "Frances Arnold Wins 2018 Nobel Prize in Chemistry | Caltech". The California Institute of Technology. Retrieved 2018-10-04.
  13. ↑ "Frances Arnold's directed evolution". American Association for the Advancement of Science. Retrieved 2018-10-03.
  14. 1 2 Freeman, David (2016-05-31). "Meet The Woman Who Launched A New Field of Scientific Study". Huffington Post. Retrieved 2018-10-04.
  15. 1 2 3 "This Nobel winner lost a son and two husbands and survived cancer". NBC News. Retrieved 2018-10-05.
  16. ↑ "Board of Directors". Illumina. Retrieved 2018-10-08.
  17. 1 2 3 4 5 6 7 8 9 10 11 "The Nobel Prize in Chemistry 2018" (PDF). The Royal Swedish Academy of Sciences. Retrieved October 3, 2018.
  18. ↑ Cirino, Patrick C.; Arnold, Frances H. (2002), Directed Molecular Evolution of Proteins, Wiley-VCH Verlag GmbH & Co. KGaA, pp. 215–243, doi:10.1002/3527600647.ch10, ISBN 978-3-527-30423-3
  19. ↑ "Scientific Background on the Nobel Prize in Chemistry 2018" (PDF). Royal Swedish Academy of Sciences. October 3, 2018.
  20. ↑ Hall, Barry G. (1978). "Experimental Evolution of a New Enzymatic Function. II. Evolution of Multiple Functions for EBG Enzyme in E. coli". Genetics. 89: 453–465.
  21. ↑ Chen, K.; Arnold, F. H. (1993-06-15). "Tuning the activity of an enzyme for unusual environments: sequential random mutagenesis of subtilisin E for catalysis in dimethylformamide". Proceedings of the National Academy of Sciences. 90 (12): 5618–5622. doi:10.1073/pnas.90.12.5618. ISSN 0027-8424.
  22. 1 2 Fernholm, Ann (October 3, 2018). "A (r)evolution in chemistry" (PDF). The Nobel Prize in Chemistry 2018: Popular Science Background.
  23. ↑ Coelho, Pedro S.; Brustad, Eric M.; Kannan, Arvind; Arnold, Frances H. (2013-01-18). "Olefin cyclopropanation via carbene transfer catalyzed by engineered cytochrome P450 enzymes". Science. 339 (6117): 307–310. doi:10.1126/science.1231434. ISSN 1095-9203. PMID 23258409.
  24. ↑ Prier, Christopher K.; Hyster, Todd K.; Farwell, Christopher C.; Huang, Audrey; Arnold, Frances H. (2016-04-04). "Asymmetric Enzymatic Synthesis of Allylic Amines: A Sigmatropic Rearrangement Strategy". Angewandte Chemie (International Ed. In English). 55 (15): 4711–4715. doi:10.1002/anie.201601056. ISSN 1521-3773. PMC 4818679. PMID 26970325.
  25. ↑ Schmidt-Dannert, C.; Umeno, D.; Arnold, F. H. (July 1, 2000). "Molecular breeding of carotenoid biosynthetic pathways". Nature Biotechnology. 18 (7): 750–753. doi:10.1038/77319. ISSN 1087-0156. PMID 10888843.
  26. ↑ May, O.; Nguyen, P. T.; Arnold, F. H. (March 1, 2000). "Inverting enantioselectivity by directed evolution of hydantoinase for improved production of L-methionine". Nature Biotechnology. 18 (3): 317–320. doi:10.1038/73773. ISSN 1087-0156. PMID 10700149.
  27. ↑ Bastian, Sabine; Liu, Xiang; Meyerowitz, Joseph T.; Snow, Christopher D.; Chen, Mike M. Y.; Arnold, Frances H. (May 2011). "Engineered ketol-acid reductoisomerase and alcohol dehydrogenase enable anaerobic 2-methylpropan-1-ol production at theoretical yield in Escherichia coli". Metabolic Engineering. 13 (3): 345–352. doi:10.1016/j.ymben.2011.02.004. ISSN 1096-7184. PMID 21515217.
  28. ↑ "Structure-guided protein recombination". The Frances H. Arnold Research Group. Retrieved October 3, 2018.
  29. ↑ Meyer, Michelle M.; Hochrein, Lisa; Arnold, Frances H. (2006-11-06). "Structure-guided SCHEMA recombination of distantly related β-lactamases". Protein Engineering, Design and Selection. 19 (12): 563–570. doi:10.1093/protein/gzl045. ISSN 1741-0134. PMID 17090554.
  30. ↑ D. S. Clarke (2002) Biotechnology and Bioengineering vol 79, no 5, page 483 "In Appreciation:James E. Bailey, 1944–2001"
  31. ↑ "Andrew E. Lange '80". Princeton Alumni Weekly. 2016-01-21. Retrieved October 3, 2018.
  32. ↑ Overbye, Dennis (2010-01-27). "Andrew Lange, Scholar of the Cosmos, Dies at 52". The New York Times. Retrieved October 3, 2018.
  33. ↑ Hamilton, Walter (July 3, 2011). "Frances Arnold: Career path of a Caltech scientist". Los Angeles Times. Retrieved September 1, 2012.
  34. 1 2 Hamilton, Walter (2011-07-03). "Frances Arnold: Career path of a Caltech scientist". Los Angeles Times. ISSN 0458-3035. Retrieved 2018-10-05.
  35. ↑ "Frances H. Arnold – Caltech Arnold Lab Reflections". arnoldlabreflections.caltech.edu. Retrieved 2018-10-04.
  36. ↑ Pipa, Siobhan (September 18, 2018). "50 engineering leaders become Fellows of the Royal Academy of Engineering". Royal Academy of Engineering. Retrieved October 4, 2018.
  37. ↑ Webb, Jonathan (2016-05-24). "Evolutionary engineer Frances Arnold wins €1m tech prize – BBC News". BBC News. Retrieved May 25, 2016.
  38. ↑ "2017 Raymond and Beverly Sackler Prize in Convergence Research". National Academy of Sciencces. Retrieved March 11, 2017.
  39. ↑ "Nobel Prize in Chemistry Honors Work That Demonstrates 'The Power of Evolution'". NPR.org. Retrieved 2018-10-04.
  40. ↑ Golgowski, Nina (2018-10-03). "Frances Arnold Becomes First American Woman To Win Nobel Prize in Chemistry". Huffington Post. Retrieved 2018-10-04.
  41. ↑ "50 engineering leaders become Fellows of the Royal Academy of Engineering". Retrieved September 21, 2018.
  42. ↑ "Pioneer of "Directed Evolution" Wins Lifetime Achievement Award | Caltech". The California Institute of Technology. Retrieved August 31, 2017.
  43. ↑ "Frances Arnold (Doctor of Science)". Dartmouth College. June 11, 2017. Retrieved June 11, 2017.
  44. 1 2 3 4 5 6 7 8 9 10 11 "Frances H. Arnold: The Division of Biology and Biological Engineering". www.bbe.caltech.edu. Retrieved 2018-10-04.
  45. ↑ Webb, Jonathan (May 25, 2016). "Evolutionary engineer Francis Arnold wins €1m tech prize". BBC News. Retrieved May 25, 2016.
  46. ↑ "Doing the right things". ETH Zurich. November 21, 2015. Retrieved November 23, 2015.
  47. ↑ "Spotlight | National Inventors Hall of Fame". Invent.org. November 21, 2013. Retrieved May 28, 2016.
  48. ↑ "Eni Award 2013 Edition". Eni. Retrieved 3 October 2018.
  49. ↑ "Honorary doctorates 1994-2016, Stockholm University". Stockholm University. October 7, 2018. Retrieved October 7, 2018.
  50. ↑ "Recipients of the Charles Stark Draper Prize for Engineering". nae.edu. National Academy of Engineering. Retrieved 3 October 2018.
  51. ↑ "President Obama Honors Nation's Top Scientists and Innovators". whitehouse.gov. December 21, 2012. Retrieved May 25, 2016.
  52. ↑ "Honorary doctorates 1994-2017, Stockholm University". Stockholm University. Retrieved October 7, 2018.
  53. ↑ "Frances H. Arnold, Enzyme Engineering Award for 2007". www.engconf.org. Retrieved June 21, 2018.
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