The code breaker, p.44
The Code Breaker, page 44
The Innovators
Kissinger
The Wise Men
Steve Jobs
American Sketches
ABOUT THE AUTHOR
WALTER ISAACSON, a professor of history at Tulane, has been CEO of the Aspen Institute, chair of CNN, and editor of Time. He is the author of Leonardo da Vinci; The Innovators; Steve Jobs; Einstein: His Life and Universe; Benjamin Franklin: An American Life; and Kissinger: A Biography, and the coauthor of The Wise Men: Six Friends and the World They Made.
SimonandSchuster.com
www.SimonandSchuster.com/Authors/Walter-Isaacson
@simonbooks
ALSO BY WALTER ISAACSON
Leonardo da Vinci
The Innovators: How a Group of Hackers, Geniuses, and Geeks Created the Digital Revolution
Steve Jobs
American Sketches
Einstein: His Life and Universe
Benjamin Franklin: An American Life
Kissinger: A Biography
The Wise Men: Six Friends and the World They Made (with Evan Thomas)
Pro and Con
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NOTES
Introduction: Into the Breach
1. Author’s interview with Jennifer Doudna. The competition was run by First Robotics, a nationwide program created by the irrepressible Segway inventor Dean Kamen.
2. Interviews, audio and video recordings, notes, and slides provided by Jennifer Doudna, Megan Hochstrasser, and Fyodor Urnov; Walter Isaacson, “Ivory Power,” Air Mail, Apr. 11, 2020.
3. See chapter 12 on the yogurt makers for a fuller discussion of the iterative process that can occur between basic researchers and technological innovation.
Chapter 1: Hilo
1. Author’s interviews with Jennifer Doudna and Sarah Doudna. Other sources for this section include The Life Scientific, BBC Radio, Sept. 17, 2017; Andrew Pollack, “Jennifer Doudna, a Pioneer Who Helped Simplify Genome Editing,” New York Times, May 11, 2015; Claudia Dreifus, “The Joy of the Discovery: An Interview with Jennifer Doudna,” New York Review of Books, Jan. 24, 2019; Jennifer Doudna interview, National Academy of Sciences, Nov. 11, 2004; Jennifer Doudna, “Why Genome Editing Will Change Our Lives,” Financial Times, Mar. 14, 2018; Laura Kiessling, “A Conversation with Jennifer Doudna,” ACS Chemical Biology Journal, Feb. 16, 2018; Melissa Marino, “Biography of Jennifer A. Doudna,” PNAS, Dec. 7, 2004.
2. Dreifus, “The Joy of the Discovery.”
3. Author’s interviews with Lisa Twigg-Smith, Jennifer Doudna.
4. Author’s interviews with Jennifer Doudna, James Watson.
5. Jennifer Doudna, “How COVID-19 Is Spurring Science to Accelerate,” The Economist, June 5, 2020.
Chapter 2: The Gene
1. This section on the history of genetics and DNA relies on Siddhartha Mukherjee, The Gene (Scribner, 2016); Horace Freeland Judson, The Eighth Day of Creation (Touchstone, 1979); Alfred Sturtevant, A History of Genetics (Cold Spring Harbor, 2001); Elof Axel Carlson, Mendel’s Legacy (Cold Spring Harbor, 2004).
2. Janet Browne, Charles Darwin, vol. 1 (Knopf, 1995) and vol. 2 (Knopf, 2002); Charles Darwin, The Journey of the Beagle, originally published 1839; Darwin, On the Origin of Species, originally published 1859. Electronic copies of Darwin’s books, letters, writings, and journals can be found at Darwin Online, darwin-online.org.uk.
3. Isaac Asimov, “How Do People Get New Ideas,” 1959, reprinted in MIT Technology Review, Oct. 20, 2014; Steven Johnson, Where Good Ideas Come From (Riverhead, 2010), 81; Charles Darwin, Autobiography, describing events of October 1838, Darwin Online, darwin-online.org.uk.
4. In addition to Mukherjee, Judson, and Sturtevant, this section on Mendel also draws from Robin Marantz Henig, The Monk in the Garden (Houghton Mifflin Harcourt, 2000).
5. Erwin Chargaff, “Preface to a Grammar of Biology,” Science, May 14, 1971.
Chapter 3: DNA
1. This section draws from my multiple interviews with James Watson over a period of years and from his book The Double Helix, originally published by Atheneum in 1968. I used The Annotated and Illustrated Double Helix, compiled by Alexander Gann and Jan Witkowski (Simon & Schuster, 2012), which includes the letters describing the DNA model and other supplemental material. This section also draws from James Watson, Avoid Boring People (Oxford, 2007); Brenda Maddox, Rosalind Franklin: The Dark Lady of DNA (HarperCollins, 2002); Judson, The Eighth Day; Mukherjee, The Gene; Sturtevant, A History of Genetics.
2. Judson says Watson was turned down at Harvard; Watson said to me and in Avoid Boring People that he was accepted but not offered a stipend or financing.
3. The youngest person to win a Nobel Prize is now Malala Yousafzai from Pakistan, who won the Peace Prize. She was shot by the Taliban and became a fighter for girls’ education.
4. Mukherjee, The Gene, 147.
5. Rosalind Franklin, “The DNA Riddle: King’s College, London, 1951–1953,” Rosalind Franklin Papers, NIH National Library of Medicine, https://profiles.nlm.nih.gov/spotlight/kr/feature/dna; Nicholas Wade, “Was She or Wasn’t She?,” The Scientist, Apr. 2003; Judson, The Eighth Day, 99; Maddox, Rosalind Franklin, 163; Mukherjee, The Gene, 149.
Chapter 4: The Education of a Biochemist
1. Author’s interviews with Jennifer Doudna.
2. Author’s interviews with Jennifer Doudna.
3. Author’s email interviews with Don Hemmes.
4. Author’s interviews with Jennifer Doudna; Jennifer A. Doudna and Samuel H. Sternberg, A Crack in Creation (Houghton Mifflin, 2017), 58; Kiessling, “A Conversation with Jennifer Doudna”; Pollack, “Jennifer Doudna.”
5. Unless otherwise noted, all Jennifer Doudna quotes in this section are from my interviews with her.
6. Sharon Panasenko, “Methylation of Macromolecules during Development in Myxococcus xanthus,” Journal of Bacteriology, Nov. 1985 (submitted July 1985).
Chapter 5: The Human Genome
1. The Department of Energy launched work on sequencing the human genome in 1986. Official funding for the Human Genome Project was in President Reagan’s 1988 budget submission. The Department of Energy and the National Institutes of Health signed a memorandum of understanding to formalize the Human Genome Project in 1990.
2. Daniel Okrent, The Guarded Gate (Scribner, 2019).
3. “Decoding Watson,” directed and produced by Mark Mannucci, American Masters, PBS, Jan. 2, 2019.
4. Author’s interviews and meetings with James Watson, Elizabeth Watson, and Rufus Watson; Algis Valiunas, “The Evangelist of Molecular Biology,” The New Atlantis, Summer 2017; James Watson, A Passion for DNA (Oxford, 2003); Philip Sherwell, “DNA Father James Watson’s ‘Holy Grail’ Request,” The Telegraph, May 10, 2009; Nicholas Wade, “Genome of DNA Discoverer Is Deciphered,” New York Times, June 1, 2007.
5. Author’s interviews with George Church, Eric Lander, and James Watson.
6. Frederic Golden and Michael D. Lemonick, “The Race Is Over,” and James Watson, “The Double Helix Revisited,” Time, July 3, 2000; author’s conversations with Al Gore, Craig Venter, James Watson, George Church, and Francis Collins.
7. Author’s own notes from the White House ceremony; Nicholas Wade, “Genetic Code of Human Life Is Cracked by Scientists,” New York Times, June 27, 2000.
Chapter 6: RNA
1. Mukherjee, The Gene, 250.
2. Jennifer Doudna, “Hammering Out the Shape of a Ribozyme,” Structure, Dec. 15, 1994.
3. Jennifer Doudna and Thomas Cech, “The Chemical Repertoire of Natural Ribozymes,” Nature, July 11, 2002.
4. Author’s interviews with Jack Szostak and Jennifer Doudna; Jennifer Doudna, “Towards the Design of an RNA Replicase,” PhD thesis, Harvard University, May 1989.
5. Author’s interviews with Jack Szostak, Jennifer Doudna.
6. Jeremy Murray and Jennifer Doudna, “Creative Catalysis,” Trends in Biochemical Sciences, Dec. 2001; Tom Cech, “The RNA Worlds in Context,” Cold Spring Harbor Perspectives in Biology, July 2012; Francis Crick, “The Origin of the Genetic Code,” Journal of Molecular Biology, Dec. 28, 1968; Carl Woese, The Genetic Code (Harper & Row, 1967), 186; Walter Gilbert, “The RNA World,” Nature, Feb. 20, 1986.
7. Jack Szostak, “Enzymatic Activity of the Conserved Core of a Group I Self-Splicing Intron,” Nature, July 3, 1986.
8. Author’s interviews with Richard Lifton, Jennifer Doudna, Jack Szostak; Greengard Prize citation for Jennifer Doudna, Oct. 2, 2018; Jennifer Doudna and Jack Szostak, “RNA-Catalysed Synthesis of Complementary-Strand RNA,” Nature, June 15, 1989; J. Doudna, S. Couture, and J. Szostak, “A Multisubunit Ribozyme That Is a Catalyst of and Template for Complementary Strand RNA Synthesis,” Science, Mar. 29, 1991; J. Doudna, N. Usman, and J. Szostak, “Ribozyme-Catalyzed Primer Extension by Trinucleotides,” Biochemistry, Mar. 2, 1993.
9. Jayaraj Rajagopal, Jennifer Doudna, and Jack Szostak, “Stereochemical Course of Catalysis by the Tetrahymena Ribozyme,” Science, May 12, 1989; Doudna and Szostak, “RNA-Catalysed Synthesis of Complementary-Strand RNA”; J. Doudna, B. P. Cormack, and J. Szostak, “RNA Structure, Not Sequence, Determines the 5’ Splice-Site Specificity of a Group I Intron,” PNAS, Oct. 1989; J. Doudna and J. Szostak, “Miniribozymes, Small Derivatives of the sunY Intron, Are Catalytically Active,” Molecular and Cell Biology, Dec. 1989.
10. Author’s interviews with Jack Szostak.
11. Author’s interview with James Watson; James Watson et al., “Evolution of Catalytic Function,” Cold Spring Harbor Symposium, vol. 52, 1987.
12. Author’s interviews with Jennifer Doudna and James Watson; Jennifer Doudna… Jack Szostak, et al., “Genetic Dissection of an RNA Enzyme,” Cold Spring Harbor Symposium, 1987, p. 173.
Chapter 7: Twists and Folds
1. Author’s interviews with Jack Szostak, Jennifer Doudna.
2. Pollack, “Jennifer Doudna.”
3. Author’s interview with Lisa Twigg-Smith.
4. Jamie Cate… Thomas Cech, Jennifer Doudna, et al., “Crystal Structure of a Group I Ribozyme Domain: Principles of RNA Packing,” Science, Sept. 20, 1996. For the first major step in the Boulder research, see Jennifer Doudna and Thomas Cech, “Self-Assembly of a Group I Intron Active Site from Its Component Tertiary Structural Domains,” RNA, Mar. 1995.
5. NewsChannel 8 report, “High Tech Shower International,” YouTube, May 29, 2018, https://www.youtube.com/watch?v=FxPFLbfrpNk&feature=share.
Chapter 8: Berkeley
1. Cate et al., “Crystal Structure of a Group I Ribozyme Domain.”
2. Author’s interviews with Jamie Cate, Jennifer Doudna.
3. Andrew Fire… Craig Mello, et al., “Potent and Specific Genetic Interference by Double-Stranded RNA in Caenorhabditis elegans,” Nature, Feb. 19, 1998.
4. Author’s interviews with Jennifer Doudna, Martin Jinek, Ross Wilson; Ian MacRae, Kaihong Zhou… Jennifer Doudna, et al., “Structural Basis for Double-Stranded RNA Processing by Dicer,” Science, Jan. 13, 2006; Ian MacRae, Kaihong Zhou, and Jennifer Doudna, “Structural Determinants of RNA Recognition and Cleavage by Dicer,” Natural Structural and Molecular Biology, Oct. 1, 2007; Ross Wilson and Jennifer Doudna, “Molecular Mechanisms of RNA Interference,” Annual Review of Biophysics, 2013; Martin Jinek and Jennifer Doudna, “A Three-Dimensional View of the Molecular Machinery of RNA Interference,” Nature, Jan. 22, 2009.
5. Bryan Cullen, “Viruses and RNA Interference: Issues and Controversies,” Journal of Virology, Nov. 2014.
6. Ross Wilson and Jennifer Doudna, “Molecular Mechanisms of RNA Interference,” Annual Review of Biophysics, May 2013.
7. Alesia Levanova and Minna Poranen, “RNA Interference as a Prospective Tool for the Control of Human Viral Infections,” Frontiers of Microbiology, Sept. 11, 2018; Ruth Williams, “Fighting Viruses with RNAi,” The Scientist, Oct. 10, 2013; Yang Li… Shou-Wei Ding, et al., “RNA Interference Functions as an Antiviral Immunity Mechanism in Mammals,” Science, Oct. 11, 2013; Pierre Maillard… Olivier Voinnet, et al., “Antiviral RNA Interference in Mammalian Cells,” Science, Oct. 11, 2013.
Chapter 9: Clustered Repeats
1. Yoshizumi Ishino… Atsuo Nakata, et al., “Nucleotide Sequence of the iap Gene, Responsible for Alkaline Phosphatase Isozyme Conversion in Escherichia coli,” Journal of Bacteriology, Aug. 22, 1987; Yoshizumi Ishino et al., “History of CRISPR-Cas from Encounter with a Mysterious Repeated Sequence to Genome Editing Technology,” Journal of Bacteriology, Jan. 22, 2018; Carl Zimmer, “Breakthrough DNA Editor Born of Bacteria,” Quanta, Feb. 6, 2015.
2. Author’s interviews with Francisco Mojica. This section also draws from Kevin Davies, “Crazy about CRISPR: An Interview with Francisco Mojica,” CRISPR Journal, Feb. 1, 2018; Heidi Ledford, “Five Big Mysteries about CRISPR’s Origins,” Nature, Jan. 12, 2017; Clara Rodríguez Fernández, “Interview with Francis Mojica, the Spanish Scientist Who Discovered CRISPR,” Labiotech, Apr. 8, 2019; Veronique Greenwood, “The Unbearable Weirdness of CRISPR,” Nautilus, Mar. 2017; Francisco Mojica and Lluis Montoliu, “On the Origin of CRISPR-Cas Technology,” Trends in Microbiology, July 8, 2016; Kevin Davies, Editing Humanity (Pegasus Books, 2020).
3. Francesco Mojica… Francisco Rodriguez-Valera, et al., “Long Stretches of Short Tandem Repeats Are Present in the Largest Replicons of the Archaea Haloferax mediterranei and Haloferax volcanii and Could Be Involved in Replicon Partitioning,” Journal of Molecular Microbiology, July 1995.
4. Email from Ruud Jansen to Francisco Mojica, Nov. 21, 2001.
5. Ruud Jansen… Leo Schouls, et al., “Identification of Genes That Are Associated with DNA Repeats in Prokaryotes,” Molecular Biology, Apr. 25, 2002.
6. Author’s interviews with Francisco Mojica.
7. Sanne Klompe and Samuel Sternberg, “Harnessing ‘a Billion Years of Experimentation,’ ” CRISPR Journal, Apr. 1, 2018; Eric Keen, “A Century of Phage Research,” Bioessays, Jan. 2015; Graham Hatfull and Roger Hendrix, “Bacteriophages and Their Genomes,” Current Opinions in Virology, Oct. 1, 2011.
8. Rodríguez Fernández, “Interview with Francis Mojica”; Greenwood, “The Unbearable Weirdness of CRISPR.”
9. Author’s interviews with Francisco Mojica; Rodríguez Fernández, “Interview with Francis Mojica”; Davies, “Crazy about CRISPR.”
10. Francisco Mojica… Elena Soria, et al., “Intervening Sequences of Regularly Spaced Prokaryotic Repeats Derive from Foreign Genetic Elements,” Journal of Molecular Evolution, Feb. 2005 (received Feb. 6, 2004; accepted Oct. 1, 2004).
11. Kira Makarova… Eugene Koonin, et al., “A Putative RNA-Interference-Based Immune System in Prokaryotes,” Biology Direct, Mar. 16, 2006.
Chapter 10: The Free Speech Movement Café
1. Author’s interviews with Jillian Banfield and Jennifer Doudna; Doudna and Sternberg, A Crack in Creation, 39; “Deep Surface Biospheres,” Banfield Lab page, Berkeley University website.
2. Author’s joint interview with Jillian Banfield and Jennifer Doudna.
3. Author’s interview with Jennifer Doudna.
Chapter 11: Jumping In
1. Author’s interviews with Blake Wiedenheft and Jennifer Doudna.
2. Kathryn Calkins, “Finding Adventure: Blake Wiedenheft’s Path to Gene Editing,” National Institute of General Medical Sciences, Apr. 11, 2016.
3. Emily Stifler Wolfe, “Insatiable Curiosity: Blake Wiedenheft Is at the Forefront of CRISPR Research,” Montana State University News, June 6, 2017.
4. Blake Wiedenheft… Mark Young, and Trevor Douglas, “An Archaeal Antioxidant: Characterization of a Dps-Like Protein from Sulfolobus solfataricus,” PNAS, July 26, 2005.
5. Author’s interview with Blake Wiedenheft.
6. Author’s interview with Blake Wiedenheft.
7. Author’s interviews with Martin Jinek, Jennifer Doudna.
8. Kevin Davies, “Interview with Martin Jínek,” CRISPR Journal, Apr. 2020.
9. Author’s interview with Martin Jinek.
10. Jinek and Doudna, “A Three-Dimensional View of the Molecular Machinery of RNA Interference”; Martin Jinek, Scott Coyle, and Jennifer A. Doudna, “Coupled 5' Nucleotide Recognition and Processivity in Xrn1-Mediated mRNA Decay,” Molecular Cell, Mar. 4, 2011.
11. Author’s interviews with Blake Wiedenheft, Martin Jinek, Rachel Haurwitz, Jennifer Doudna.
12. Author’s interviews with Blake Wiedenheft, Jennifer Doudna; Blake Wiedenheft, Kaihong Zhou, Martin Jinek… Jennifer Doudna, et al., “Structural Basis for DNase Activity of a Conserved Protein Implicated in CRISPR-Mediated Genome Defense,” Structure, June 10, 2009.
13. Jinek and Doudna, “A Three-Dimensional View of the Molecular Machinery of RNA Interference.”
14. Author’s interviews with Martin Jinek, Blake Wiedenheft, Jennifer Doudna.
15. Wiedenheft et al., “Structural Basis for DNase Activity of a Conserved Protein.”
Chapter 12: The Yogurt Makers
1. Vannevar Bush, “Science, the Endless Frontier,” Office of Scientific Research and Development, July 25, 1945.
2. Matt Ridley, How Innovation Works (Harper Collins, 2020), 282.
