The Code Breaker, page 46
5. Author’s interviews with Rodger Novak and Emmanuelle Charpentier.
6. Author’s interview with Andy May.
7. Hemme, “Fireside Chat with Rodger Novak.”
8. Author’s interviews with Jennifer Doudna.
9. Editas Medicine, SEC 10-K filing 2016 and 2019; John Carroll, “Biotech Pioneer in ‘Gene Editing’ Launches with $43M in VC Cash,” FierceBiotech, Nov. 25, 2013.
10. Author’s interviews with Jennifer Doudna, Rachel Haurwitz, Erik Sontheimer, and Luciano Marraffini.
Chapter 29: Mon Amie
1. Author’s interviews with Jennifer Doudna, Emmanuelle Charpentier, and Martin Jinek; Martin Jinek… Samuel Sternberg… Kaihong Zhou… Emmanuelle Charpentier, Eva Nogales, Jennifer A. Doudna, et al., “Structures of Cas9 Endonucleases Reveal RNA-Mediated Conformational Activation,” Science, Mar. 14, 2014.
2. Jennifer Doudna and Emmanuelle Charpentier, “The New Frontier of Genome Engineering with CRISPR-Cas9,” Science, Nov. 28, 2014.
3. Author’s interviews with Jennifer Doudna and Emmanuelle Charpentier.
4. Hemme, “Fireside Chat with Rodger Novak”; author’s interview with Rodger Novak.
5. Author’s interview with Rodolphe Barrangou.
6. Davies, Editing Humanity, 96.
7. Author’s interview with Jennifer Doudna; “CRISPR Timeline,” Broad Institute website, broadinstitute.org.
8. Author’s interview with Eric Lander; Breakthrough Prize ceremony, Mar. 19, 2015.
9. Author’s interviews with Jennifer Doudna, George Church; Gairdner Awards ceremony, Oct. 27, 2016.
Chapter 30: The Heroes of CRISPR
1. Author’s interviews with Eric Lander and Emmanuelle Charpentier.
2. Lander, “The Heroes of CRISPR.”
3. Michael Eisen, “The Villain of CRISPR,” It Is Not Junk, Jan. 25, 2016.
4. “Heroes of CRISPR,” eighty-four comments, PubPeer, https://pubpeer.com/publications/D400145518C0A557E9A79F7BB20294; Sharon Begley, “Controversial CRISPR History Set Off an Online Firestorm,” Stat, Jan. 19, 2016.
5. Nathaniel Comfort, “A Whig History of CRISPR,” Genotopia, Jan. 18, 2016; @nccomfort, “I made a hashtag that became a thing! #Landergate,” Twitter, Jan. 27, 2016.
6. Antonio Regalado, “A Scientist’s Contested History of CRISPR,” MIT Technology Review, Jan. 19, 2016.
7. Ruth Reader, “These Women Helped Create CRISPR Gene Editing. So Why Are They Written Out of Its History?,” Mic, Jan. 22, 2016; Joanna Rothkopf, “How One Man Tried to Write Women Out of CRISPR, the Biggest Biotech Innovation in Decades,” Jezebel, Jan. 20, 2016.
8. Stephen Hall, “The Embarrassing, Destructive Fight over Biotech’s Big Breakthrough,” Scientific American, Feb. 4, 2016.
9. Tracy Vence, “ ‘Heroes of CRISPR’ Disputed,” The Scientist, Jan. 19, 2016.
10. Author’s interview with Jack Szostak.
11. Eric Lander, email to the Broad Institute staff, Jan. 28, 2016.
12. Joel Achenbach, “Eric Lander Talks CRISPR and the Infamous Nobel ‘Rule of Three,’ ” Washington Post, Apr. 21, 2016.
Chapter 31: Patents
1. Diamond v. Chakrabarty, 447 U.S. 303, U.S. Supreme Court, 1980; Douglas Robinson and Nina Medlock, “Diamond v. Chakrabarty: A Retrospective on 25 Years of Biotech Patents,” Intellectual Property & Technology Law Journal, Oct. 2005.
2. Michael Eisen, “Patents Are Destroying the Soul of Academic Science,” it is NOT junk (blog), Feb. 20, 2017. See also Alfred Engelberg, “Taxpayers Are Entitled to Reasonable Prices on Federally Funded Drug Discoveries,” Modern Healthcare, July 18, 2018.
3. Author’s interview with Eldora Ellison.
4. Martin Jinek, Jennifer Doudna, Emmanuelle Charpentier, and Krzysztof Chylinski, U.S. Patent Application 61/652,086, “Methods and Compositions, for RNA-Directed Site-Specific DNA Modification,” filed May 25, 2012; Jacob Sherkow, “Patent Protection for CRISPR,” Journal of Law and the Biosciences, Dec. 7, 2017.
5. “CRISPR-Cas Systems and Methods for Altering Expressions of Gene Products,” provisional application No. 61/736,527, filed on Dec. 12, 2012, which in 2014 resulted in U.S. Patent No. 8,697,359. This application, later revised, included Luciano Marraffini as well as Feng Zhang, Le Cong, and Shuailiang Lin as inventors.
6. The main patent application and related filings of Zhang/Broad can be found through the U.S. Patent Office as U.S. Provisional Patent Application No. 61/736,527. The Doudna/Charpentier/Berkeley filings are under U.S. Provisional Patent Application No. 61/652,086. A good guide to the patent issues is the work of Jacob Sherkow of New York Law School, which includes “Law, History and Lessons in the CRISPR Patent Conflict,” Nature Biotechnology, Mar. 2015; “Patents in the Time of CRISPR,” Biochemist, June 2016; “Inventive Steps: The CRISPR Patent Dispute and Scientific Progress,” EMBO Reports, May 23, 2017; “Patent Protection for CRISPR.”
7. Author’s interviews with George Church, Jennifer Doudna, Erik Lander, and Feng Zhang.
8. “CRISPR-Cas Systems and Methods for Altering Expressions of Gene Products,” provisional application No. 61/736,527.
9. Author’s interviews with Luciano Marraffini.
10. Author’s interviews with Feng Zhang and Eric Lander; Lander, “Heroes of CRISPR.”
11. U.S. Patent No. 8,697,359.
12. Author’s interviews with Andy May and Jennifer Doudna.
13. Provisional patent application U.S. 2012/61652086P and published patent application U.S. 2014/0068797A1 of Doudna et al.; Provisional patent application U.S. 2012/61736527P (Dec. 12, 2012) and granted patent US 8,697,359 B1 (Apr. 15, 2014) of Zhang et al.
14. “Suggestion of Interference” and “Declaration of Dana Carroll, PhD, in Support of Suggestion of Interference,” in re Patent Application of Jennifer Doudna et al., serial no. 2013/842859, U.S. Patent and Trademark Office, Apr. 10 and 13, 2015; Mark Summerfield, “CRISPR—Will This Be the Last Great US Patent Interference?,” Patentology, July 11, 2015; Jacob Sherkow, “The CRISPR Patent Interference Showdown Is On,” Stanford Law School blog, Dec. 29, 2015; Antonio Regalado, “CRISPR Patent Fight Now a Winner-Take-All Match,” MIT Technology Review, Apr. 15, 2015.
15. Feng Zhang, “Declaration,” in re Patent Application of Feng Zhang, Serial no. 2014/054,414, Jan. 30, 2014, provided privately to the author.
16. In re Dow Chemical Co., 837 F.2d 469, 473 (Fed. Cir. 1988).
17. Jacob Sherkow, “Inventive Steps: The CRISPR Patent Dispute and Scientific Progress,” EMBO Reports, May 23, 2017; Broad et al. contingent responsive motion 6 for benefit of Broad et al. Application 61/736,527, USPTO, June 22, 2016; University of California et al., Opposition motion 2, Patent Interference case 106,048, USPTO, Aug. 15, 2016 (Opposing Broad’s Allegations of No Interference-in-Fact).
18. Alessandra Potenza, “Who Owns CRISPR?,” The Verge, Dec. 6, 2016; Jacob Sherkow, “Biotech Trial of the Century Could Determine Who Owns CRISPR,” MIT Technology Review, Dec. 7, 2016; Sharon Begley, “CRISPR Court Hearing Puts University of California on the Defensive,” Stat, Dec. 6, 2016.
19. Transcript of oral arguments before the patent trial board, Dec. 6, 2016, Patent Interference Case 106,048, U.S. Patent and Trademark Office.
20. Jennifer Doudna interview, Catalyst, UC Berkeley College of Chemistry, July 10, 2014.
21. Berkeley substantive motion 4, Patent Interference Case 106,048, May 23, 2016. See also Broad substantive motions 2, 3, and 5.
22. Patent Trial Board Judgment and Decision on Motions, Patent Interference Case 106,048, Feb. 15, 2017.
23. Judge Kimberly Moore, decision, Patent Interference Case 106,048, United States Court of Appeals for the Federal Circuit, Sept. 10, 2018.
24. Author’s interviews with Eldora Ellison.
25. Patent Interference No. 106,115, Patent Trial and Appeal Board, June 24, 2019.
26. Oral argument, Patent Interference No. 106,115, Patent Trial and Appeal Board, May 18, 2020.
27. “Methods and Compositions for RNA-Directed Target DNA Modification,” European Patent Office, patent EP2800811, granted Apr. 7, 2017; Jef Akst, “UC Berkeley Receives CRISPR Patent in Europe,” The Scientist, Mar. 24, 2017; Sherkow, “Inventive Steps.”
28. Author’s interviews with Luciano Marraffini; “Engineering of Systems, Methods, and Optimized Guide Compositions for Sequence Manipulation,” European Patent Office, patent EP2771468; Kelly Servick, “Broad Institute Takes a Hit in European CRISPR Patent Struggle,” Science, Jan. 18, 2018; Rory O’Neill, “EPO Revokes Broad’s CRISPR Patent,” Life Sciences Intellectual Property Review, Jan. 16, 2020.
29. Author’s interview with Andy May.
Chapter 32: Therapies
1. Rob Stein, “In a First, Doctors in U.S. Use CRISPR Tool to Treat Patient with Genetic Disorder,” Morning Edition, NPR, July 29, 2019; Rob Stein, “A Young Mississippi Woman’s Journey through a Pioneering Gene-Editing Experiment,” All Things Considered, NPR, Dec. 25, 2019.
2. “CRISPR Therapeutics and Vertex Announce New Clinical Data,” CRISPR Therapeutics, June 12, 2020.
3. Rob Stein, “A Year In, 1st Patient to Get Gene-Editing for Sickle Cell Disease Is Thriving,” Morning Edition, NPR, June 23, 2020.
4. Author’s interview with Emmanuelle Charpentier.
5. Author’s interview with Jennifer Doudna.
6. “Proposal for an IGI Sickle Cell Initiative,” Innovative Genomics Institute, February 2020.
7. Preetika Rana, Amy Dockser Marcus, and Wenxin Fan, “China, Unhampered by Rules, Races Ahead in Gene-Editing Trials,” Wall Street Journal, Jan. 21, 2018.
8. David Cyranoski, “CRISPR Gene-Editing Tested in a Person for the First Time,” Nature, Nov. 15, 2016.
9. Jennifer Hamilton and Jennifer Doudna, “Knocking Out Barriers to Engineered Cell Activity,” Science, Feb. 6, 2020; Edward Stadtmauer… Carl June, et al., “CRISPR-Engineered T Cells in Patients with Refractory Cancer,” Science, Feb. 6, 2020.
10. “CRISPR Diagnostics in Cancer Treatments,” Mammoth Biosciences website, June 11, 2019.
11. “Single Ascending Dose Study in Participants with LCA10,” ClinicalTrials.gov, Mar. 13, 2019, identifier: NCT03872479; Morgan Maeder… and Haiyan Jiang, “Development of a Gene-Editing Approach to Restore Vision Loss in Leber Congenital Amaurosis Type 10,” Nature, Jan. 21, 2019.
12. Marilynn Marchione, “Doctors Try 1st CRISPR Editing in the Body for Blindness,” AP, Mar. 4, 2020.
13. Sharon Begley, “CRISPR Babies’ Lab Asked U.S. Scientist for Help to Disable Cholesterol Gene in Human Embryos,” Stat, Dec. 4, 2018; Anthony King, “A CRISPR Edit for Heart Disease,” Nature, Mar. 7, 2018.
14. Matthew Porteus, “A New Class of Medicines through DNA Editing,” New England Journal of Medicine, Mar. 7, 2019; Sharon Begley, “CRISPR Trackr: Latest Advances,” Stat Plus.
Chapter 33: Biohacking
1. Josiah Zayner, “DIY Human CRISPR Myostatin Knock-Out,” YouTube, Oct. 6, 2017; Sarah Zhang, “Biohacker Regrets Injecting Himself with CRISPR on Live TV,” The Atlantic, Feb. 20, 2018; Stephanie Lee, “This Guy Says He’s the First Person to Attempt Editing His DNA with CRISPR,” BuzzFeed, Oct. 14, 2017.
2. Kate McLean and Mario Furloni, “Gut Hack,” New York Times op-doc, Apr. 11, 2017; Arielle Duhaime-Ross, “A Bitter Pill,” The Verge, May 4, 2016.
3. “About us,” The Odin, https://www.the-odin.com/about-us/; author’s interviews with Josiah Zayner.
4. Author’s interviews with Josiah Zayner and Kevin Doxzen.
5. Author’s interview with Josiah Zayner. See also Josiah Zayner, “CRISPR Babies Scientist He Jiankui Should Not Be Villainized,” Stat, Jan. 2, 2020.
Chapter 34: DARPA and anti-CRISPR
1. Heidi Ledford, “CRISPR, the Disruptor,” Nature, June 3, 2015. Danilo Maddalo… and Andrea Ventura, “In vivo Engineering of Oncogenic Chromosomal Rearrangements with the CRISPR/Cas9 System,” Nature, Oct. 22, 2014; Sidi Chen, Neville E. Sanjana… Feng Zhang, and Phillip A. Sharp, “Genome-wide CRISPR Screen in a Mouse Model of Tumor Growth and Metastasis,” Cell, Mar. 12, 2015.
2. James Clapper, “Threat Assessment of the U.S. Intelligence Community,” Feb. 9, 2016; Antonio Regalado, “The Search for the Kryptonite That Can Stop CRISPR,” MIT Technology Review, May 2, 2019; Robert Sanders, “Defense Department Pours $65 Million into Making CRISPR Safer,” Berkeley News, July 19, 2017.
3. Defense Advanced Research Projects Agency, “Building the Safe Genes Toolkit,” July 19, 2017.
4. Author’s interview with Jennifer Doudna.
5. Author’s interview with Joe Bondy-Denomy; Joe Bondy-Denomy, April Pawluk… Alan R. Davidson, et al., “Bacteriophage Genes That Inactivate the CRISPR/Cas Bacterial Immune System,” Nature, Jan. 17, 2013; Elie Dolgin, “Kill Switch for CRISPR Could Make Gene Editing Safer,” Nature, Jan. 15, 2020.
6. Jiyung Shin… Joseph Bondy-Denomy, and Jennifer Doudna, “Disabling Cas9 by an Anti-CRISPR DNA Mimic,” Science Advances, July 12, 2017.
7. Nicole D. Marino… and Joseph Bondy-Denomy, “Anti-CRISPR Protein Applications: Natural Brakes for CRISPR-Cas Technologies,” Nature Methods, Mar. 16, 2020.
8. Author’s interview with Fyodor Urnov; Emily Mullin, “The Defense Department Plans to Build Radiation-Proof CRISPR Soldiers,” One Zero, Sept. 27, 2019.
9. Author’s interviews with Jennifer Doudna and Gavin Knott.
10. Author’s interviews with Josiah Zayner.
Chapter 35: Rules of the Road
1. Robert Sinsheimer, “The Prospect of Designed Genetic Change,” Engineering and Science, Caltech, Apr. 1969.
2. Bentley Glass, Presidential Address to the AAAS, Dec. 28, 1970, Science, Jan. 8, 1971.
3. John Fletcher, The Ethics of Genetic Control: Ending Reproductive Roulette (Doubleday, 1974), 158.
4. Paul Ramsey, Fabricated Man (Yale, 1970), 138.
5. Ted Howard and Jeremy Rifkin, Who Should Play God? (Delacorte, 1977), 14; Dick Thompson, “The Most Hated Man in Science,” Time, Dec. 4, 1989.
6. Shane Crotty, Ahead of the Curve (University of California, 2003), 93; Mukherjee, The Gene, 225.
7. Paul Berg et al., “Potential Biohazards of Recombinant DNA Molecules,” Science, July 26, 1974.
8. Author’s interview with David Baltimore; Michael Rogers, “The Pandora’s Box Conference,” Rolling Stone, June 19, 1975; Michael Rogers, Biohazard (Random House, 1977); Crotty, Ahead of the Curve, 104–8; Mukherjee, The Gene, 226–30; Donald S. Fredrickson, “Asilomar and Recombinant DNA: The End of the Beginning,” in Biomedical Politics (National Academies Press, 1991); Richard Hindmarsh and Herbert Gottweis, “Recombinant Regulation: The Asilomar Legacy 30 Years On,” Science as Culture, Fall 2005; Daniel Gregorowius, Nikola Biller-Andorno, and Anna Deplazes-Zemp, “The Role of Scientific Self-Regulation for the Control of Genome Editing in the Human Germline,” EMBO Reports, Feb. 20, 2017; Jim Kozubek, Modern Prometheus (Cambridge, 2016), 124.
9. Author’s interviews with James Watson and David Baltimore.
10. Paul Berg et al., “Summary Statement of the Asilomar Conference on Recombinant DNA Molecules,” PNAS, June 1975.
11. Paul Berg, “Asilomar and Recombinant DNA,” The Scientist, Mar. 18, 2002.
12. Hindmarsh and Gottweis, “Recombinant Regulation,” 301.
13. Claire Randall, Rabbi Bernard Mandelbaum, and Bishop Thomas Kelly, “Message from Three General Secretaries to President Jimmy Carter,” June 20, 1980.
14. Morris Abram et al., Splicing Life, President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, Nov. 16, 1982.
15. Alan Handyside et al., “Birth of a Normal Girl after in vitro Fertilization and Preimplantation Diagnostic Testing for Cystic Fibrosis,” New England Journal of Medicine, Sept. 1992.
16. Roger Ebert, Gattaca review, Oct. 24, 1997, rogerebert.com.
17. Gregory Stock and John Campbell, Engineering the Human Germline (Oxford, 2000), 73–95; author’s interviews with James Watson; Gina Kolata, “Scientists Brace for Changes in Path of Human Evolution,” New York Times, Mar. 21, 1998.
18. Steve Connor, “Nobel Scientist Happy to ‘Play God’ with DNA,” The Independent, May 17, 2000.
19. Lee Silver, Remaking Eden (Avon, 1997), 4.
20. Lee Silver, “Reprogenetics: Third Millennium Speculation,” EMBO Reports, Nov. 15, 2000.
21. Gregory Stock, Redesigning Humans: Our Inevitable Genetic Future (Houghton Mifflin, 2002), 170.
22. Council of Europe, “Oviedo Convention and Its Protocols,” April 4, 1997.
23. Sheryl Gay Stolberg, “The Biotech Death of Jesse Gelsinger,” New York Times, Nov. 28, 1999.
24. Meir Rinde, “The Death of Jesse Gelsinger,” Science History Institute, June 4, 2019.
25. Harvey Flaumenhaft, “The Career of Leon Kass,” Journal of Contemporary Health Law & Policy, 2004; “Leon Kass,” Conversations with Bill Kristol, Dec. 2015, https://conversationswithbillkristol.org/video/leon-kass/.
26. Leon Kass, “What Price the Perfect Baby?,” Science, July 9, 1971; Leon Kass, “Review of Fabricated Man by Paul Ramsey,” Theology Today, Apr. 1, 1971; Leon Kass, “Making Babies: the New Biology and the Old Morality,” Public Interest, Winter 1972.
27. Michael Sandel, “The Case against Perfection,” The Atlantic, Apr. 2004; Michael Sandel, The Case Against Perfection (Harvard, 2007).
28. Francis Fukuyama, Our Posthuman Future (Farrar, Straus and Giroux, 2000), 10.
29. Leon Kass et al., Beyond Therapy: Biotechnology and the Pursuit of Happiness, report of the President’s Council on Bioethics, October 2003.
Chapter 36: Doudna Steps In
1. Doudna and Sternberg, A Crack in Creation, 198; Michael Specter, “Humans 2.0,” New Yorker, Nov. 16, 2015; author’s interview with Jennifer Doudna.
2. Author’s interviews with Sam Sternberg and Lauren Buchman.
