CRISPR

CRISPR People: The Science and Ethics of Editing Humans

by Henry T. Greely  · 22 Jan 2021

Stone Serif Std and PF DIN by New Best-set Typesetters Ltd. Library of Congress Cataloging-in-Publication Data Names: Greely, Henry T., author. Title: CRISPR people : the science and ethics of editing humans / Henry T. Greely. Description: Cambridge, Massachusetts : The MIT Press, [2021] | Includes bibliographical references and index. Identifiers:

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regularly interspaced short palindromic repeats”) to change the DNA of human embryos that would be transferred into women’s uteruses for possible pregnancy and birth—“CRISPR babies.” A quick look at my (exploding) Twitter feed almost immediately led me to an Associated Press (AP) story by Marilynn Marchione. That story

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what He actually did, as much as we know, which is still surprisingly little. The second and third chapters explain human germline genome editing and CRISPR. The fourth and fifth chapters describe the ethical discussions about and legal status of human germline genome editing before November 25, 2018. Part II

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just a shortcut that saves writers, especially headline writers, a few characters. And, finally, you may read of human germline genome (or gene or DNA) “CRISPRing” because that is the best technology at our disposal today. But not, perhaps, tomorrow. Usually, however, whatever words they use, articles about the He

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but close. And we should all benefit from it, though which scientists, universities, and companies will particularly benefit remains to be seen. As noted earlier, CRISPR is also an acronym, standing for “clustered regularly interspaced short palindromic repeats.”1 This is a case where my distaste for COAs gives way. Not

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same kind of spacer arrangement. Mojica pushed to understand this phenomenon, publishing several articles on its mechanism as he understood more about it. Naming of CRISPR Others also were investigating the same repeating bits of DNA inside bacterial cells, but the phenomenon had no accepted name. In 2000, Mojica published

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“spacers interspersed direct repeats,” or SPIDR.6 Mojica says, The potential naming conflict was solved after mutual agreement of the two research groups to use CRISPR (pronounced krisper) after “Clustered Regularly Interspaced Short Palindromic Repeats.” Jansen immediately accepted the new definition and acronym rather than the other, less descriptive or

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family and to avoid confusing nomenclature, Mojica et al. and our research group have agreed to use in this report and future publication the acronym CRISPR, which reflects the characteristic features of this family of clustered regularly interspaced short palindromic repeats.8 (The article’s acknowledgments section states, “We enjoyed

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Institute (a collaboration between Harvard University and the Massachusetts Institute of Technology, with the counterintuitive pronunciation of “Brōd,” with a long “o”), showed that CRISPR could also work in cells from “eukaryotes,” the more complicated forms of life that include amoebas, fungi, plants, and animals.26 In the same issue

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were not discussed in any detail at the meeting, at least not openly, rumors abounded that Chinese scientists were about to announce that they used CRISPR to modify human embryos. Those rumors, whatever we thought of them, added a certain urgency to the meeting. The group reached consensus surprisingly quickly,

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genetic disease, and the attendant ethical, social, and legal implications of genome modification. Encourage and support transparent research to evaluate the efficacy and specificity of CRISPR-Cas9 genome engineering technology in human and nonhuman model systems relevant to its potential applications for germline gene therapy . . . Convene a globally representative group

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agencies and interest groups, to further consider these important issues, and where appropriate, recommend policies. In the meantime, another article on the use of CRISPR in humans had appeared online the week before in Nature, calling for an absolute ban on germline modifications in humans, in part expressly to prevent

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the shoe dropped with the publication of an article by Chinese scientists, discussed in chapter 1, reporting that they had, with some limited success, used CRISPR to edit (nonviable) human embryos.22 This narrative should sound familiar from the discussion of Asilomar. A small group of leading researchers meets at a

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next morning, November 26, in Hong Kong), Regalado posted an article on the website of the MIT Technology Review entitled “Exclusive: Chinese Scientists Are Creating CRISPR Babies.”1 The article reported, According to Chinese medical documents posted online this month . . . a team at the Southern University of Science and Technology,

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following genome editing, and human genomics more broadly, in China for several years. Regalado wrote, The clinical trial documents describe a study in which CRISPR is employed to modify human embryos before they are transferred into women’s uteruses. The scientist behind the effort, He Jiankui, did not reply to

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were still so fresh that the diners sat in the restaurant without being disturbed. “He arrived almost defiant,” says Jennifer Doudna, who did landmark CRISPR work at the University of California (UC), Berkeley. She and the other conference organizers politely asked He questions about the scientific details and rationale of

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language was restrained compared with the assessments of some critics. Ed Yong hit some of the high points in an article in The Atlantic: The CRISPR pioneer Jennifer Doudna says she was “horrified,” NIH Director Francis Collins said the experiment was “profoundly disturbing,” and even Julian Savulescu, an ethicist who

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its full, 316-word English translation: Regarding the recent news from domestic and foreign media on human embryo gene-editing and two babies born using CRISPR technology, as rational human beings, with respect for scientific theories and concerns regarding the future scientific developments in China, our statement is as follows:

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the experiment conducted directly on human beings. We have much to debate inside the scientific community about the accuracy and off-target-effects brought by CRISPR. Any attempts to alter human embryos and make babies carry huge risks without strict examination beforehand. It is scientifically possible, but scientists and medical

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parents of the Asilomar meeting on recombinant DNA; Emmanuelle Charpentier and Feng Zhang, two of the people viewed as among the most important inventors of CRISPR; Eric Lander, the director of the scientifically powerful Broad Institute, a joint venture of Harvard and the Massachusetts Institute of Technology; and 14 others.

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high-risk biomedical technologies, [and which] is at the center of a regulatory shakeup Chinese authorities are planning in the aftermath of the widely condemned “CRISPR babies” experiment. . . . The technologies that will be regulated by the ethics committee are often new and are deemed risky either because of safety or

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strains is presented. This method is shown to be able to identify a cluster around an incipient dominant strain before it becomes dominant. Recently, CRISPR has been suggested to provide adaptive immune response to bacteria. A population dynamics model is proposed that explains the biological observation that the leader-proximal

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Lab Asked U.S. Scientist for Help to Disable Cholesterol Gene in Human Embryos,” STAT, December 4, 2018, https://www.statnews.com/2018/12/04/crispr-babies-cholesterol-gene-editing. 28. The names of genes and proteins are deeply unintuitive. One useful convention, though, observed in most of the scientific literature

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Repeats among Prokaryotes,” OMICS 6, no. 1 (2002): 23–33, https://doi.org/10.1089/15362310252780816. 7. Mojica and Rodriguez-Valera, “The Discovery of CRISPR in Archaea and Bacteria.” 8. Ruud Jansen, Jan D. A. van Embden, Wim Gaastra, et al., “Identification of Genes That Are Associated with DNA Repeats

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no. 6 (2018): 1239–1259, https://doi.org/10.1016/j.cell.2017.11.032. 21. See R. Alta Charo and Henry T. Greely, “CRISPR Critters and CRISPR Cracks,” American Journal of Bioethics 15: 12, 11–17 (2015); Henry T. Greely, “The WorldPost: We Need to Talk about Genetically Modifying Animals,” Washington

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and Hank Greely, “Why the Panic over ‘Designer Babies’ Is the Wrong Worry,” LeapsMag (October 30, 2017), https://leapsmag.com/much-ado-about-nothing-much-crispr-for-human-embryo-editing. 22. Martin Jinek, Krzysztof Chylinski, Ines Fonfara, et al., “A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial Immunity,” Science

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an important improvement on what Šikšnys described. Bacteria deploy two different and physically separate kinds of RNA (called a tracrRNA and a crRNA) to use CRISPR; Doudna and Charpentier showed how those two RNAs could be efficiently combined into one construct (the “dual-RNAs” of the last sentence of their

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, “Experiments to Gene-Edit Babies Are ‘Criminally Reckless,’ Says Stanford Bio-ethicist,” CNBC, November 26, 2018, https://www.cnbc.com/2018/11/26/chinese-crispr-baby-gene-editing-criminally-reckless-bio-ethicist.html. 5. Lauran Neergaard and Malcolm Ritter, “Q&A on Scientist’s Bombshell Claim of Gene-Edited Babies

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China Gene-Edited Baby Work,” Associated Press, February 7, 2019, https://www.apnews.com/8480105385f64ccf98c88d1f809a8bed. 20. Regalado, “Stanford Will Investigate Its Role in the Chinese CRISPR Baby Debacle.” 21. Pam Belluck, “Stanford Clears Professor of Helping with Gene-Edited Babies Experiment,” New York Times, April 16, 2019, https://www.nytimes.com

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it’s worth, I think her reporting on Deem has been exceptional. 44. Andrew Joseph, “Rice University Opens Investigation into Researcher Who Worked on CRISPR’d Baby Project,” STAT, November 26, 2018, https://www.statnews.com/2018/11/26/rice-university-opens-investigation-into-researcher-who-worked-on-crisprd-baby

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): 396–397. 55. Qiu, “American Scientist Played More Active Role.” 56. Qiu, “American Scientist Played More Active Role (“Deem’s possible involvement in the CRISPR babies experiment has led the Hong Kong university to review the contract, which is now ‘pending on the result of the investigation undergoing at the

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Issues Plagued Newly Surfaced Paper.” 58. Qiu, “American Scientist Played More Active Role.” 59. Qiu, “American Scientist Played More Active Role.” 60. Regalado, “China’s CRISPR Babies: Read Exclusive Excerpts from the Unseen Original Research.” 61. The Princess Bride, directed by Rob Reiner (20th Century Fox, 1987). Chapter 9 1. Christina

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Atlantic, November 26, 2018, https://www.theatlantic.com/science/archive/2018/11/first-gene-edited-babies-have-allegedly-been-born-in-china/576661; Yong, “The CRISPR Baby Scandal Gets Worse by the Day.” 41. David Cyranowski and Heidi Ledford, “Genome-Edited Baby Claim Provokes International Outcry,” Nature, November 26, 2018,

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of Science and Technology, He’s (former) employer, but an English translation can be found at “Informed Consent,” https://www.sciencemag.org/sites/default/files/crispr_informed-consent.pdf. See also Derek Lowe, “After Such Knowledge,” In the Pipeline, November 26, 2018, https://blogs.sciencemag.org/pipeline/archives/2018/11/

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babies-china. 66. Marilynn Marchione, “Chinese Researcher Claims First Gene-Edited Babies,” Associated Press, November 26, 2018, https://www.apnews.com/4997bb7aa36c45449b488e19ac83e86d. 67. Yong, “The CRISPR Baby Scandal Gets Worse by the Day.” 68. Harmonicare Medical Holdings Ltd, “Clarification Announcement Regarding Certain Media Reports,” November 27, 2018, https://www.sciencemag.org

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/sites/default/files/crispr_clarification.pdf. 69. Xinhua, “Guangdong Releases Preliminary Investigation Result of Gene-Edited Babies.” 70. Xinhua, “Guangdong Releases Preliminary Investigation Result of Gene-Edited Babies.”

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71. Henry T. Greely, “CRISPR’d Babies: Human Germline Genome Editing in the ‘He Jiankui Affair,’” Journal of Law and the Biosciences 6, no. 1 (2019): 111–183; Marilynn Marchione

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died or was subject to great bodily harm. The Child Abuse and Neglect Reporting Act, California Penal Code §§ 11164–11174.3. 12. Stanford Law School, “CRISPR’d Babies—A Discussion with Matt Porteus,” February 7, 2019, https://www.youtube.com/watch?v=Db6SQgsp6Zo. 13. David Baltimore, Paul Berg, Michael Botchan,

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Genome Editing,” November 26, 2018, https://www.broadinstitute.org/news/broad-scientists-and-geneticists-discuss-issues-raised-clinical-germline-genome-editing. 23. Robin Lovell-Badge, “CRISPR Babies: A View from the Centre of the Storm,” Development 146, no. 3 (2019), https://doi.org/10.1242/dev.175778. 24. Victor J.

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Rogue,” STAT, October 16, 2019, https://www.statnews.com/2019/10/16/russia-health-ministry-calls-human-embryo-editing-premature. 49. David Cyranoski, “Russian ‘CRISPR-Baby’ Scientist Has Started Editing Genes in Human Eggs with Goal of Altering Deaf Gene, Nature 574 (October 24, 2019): 465–466, https://www.nature

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, in February 2019 Antonio Regalado published a piece about another person who was planning to do germline gene editing, not on embryos but through injecting CRISPR into men’s testicles. Antonio Regalado, “The DIY Designer Baby Project Funded with Bitcoin,” MIT Technology Review, February 1, 2019, https://www.technologyreview.com

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Sarah Zhang, “Would You Buy a Genetically-Engineered Cashmere Sweater?,” The Atlantic, October 26, 2016, https://www.theatlantic.com/health/archive/2016/10/cashmere-goat-crispr/505163. 56. Antonio Regalado, “First Gene-Edited Dogs Reported in China,” MIT Technology Review, October 19, 2015, https://www.technologyreview.com/s/542616/first-

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, 2019, https://www.statnews.com/2019/03/05/china-creating-national-medical-ethics-committee. 68. David Cyranoski, “China Set to Introduce Gene-Editing Regulation Following CRISPR-Baby Furore,” Nature (May 20, 2019), https://www.nature.com/articles/d41586-019-01580-1. 69. Reed Smith, “The Adoption of the Chinese Civil

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. I strongly suspect Churchill made the speaker up for rhetorical purposes. Conclusion 1. William Shakespeare, Macbeth, act 1, sc. 7. 2. Henry T. Greely, “CRISPR’d Babies: Human Germline Genome Editing in the ‘He Jiankui Affair,’” Journal of Law and the Biosciences 6, no. 1 (2019): 111–183, 183. Index

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Society for Reproductive Medicine (ASRM), 266–267 Annas, George, 162 Archaea, 37, 39 Asilomar. See Asilomar Conference Asilomar Conference, 49, 53, 56–59 parallels with CRISPR discussion, 61–62, 65–66 Asilomar Conference Grounds, 57–58 Atlantic, The, 110, 157 Autosomal dominant, 226–227. See also Autosomal recessive; Mendelian genetics and

Editing Humanity: The CRISPR Revolution and the New Era of Genome Editing

by Kevin Davies  · 5 Oct 2020  · 741pp  · 164,057 words

. Tools to control neurons, map the architecture of the cell nucleus, and conduct a liquid biopsy of DNA fragments circulating in the bloodstream. But CRISPR has changed science in a profound way: the technique caught fire, its simplicity, flexibility, and affordability catching the imagination of researchers around the world

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in a dazzling democratization of technology. CRISPR wasn’t the result of a dedicated applied engineering effort. Instead it is the culmination of decades of investment in basic biomedical research, supporting dozens

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at curing devastating diseases such as his own affliction, a slowly progressive form of amyotrophic lateral sclerosis. Hawking believed scientists would use techniques such as CRISPR to modify or enhance traits like intelligence, memory, and longevity—violating the law if necessary. These “superhumans” would be available to wealthy elites, putting

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the Year.” ZFNs and another gene-editing platform called TALENs have their admirers, but were too fussy and expensive to break out the way CRISPR has. CRISPR takes the premise of other forms of genome editing and (in the parlance of Spinal Tap) turns it up to 11. From Australia to

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.”11 Six months later, Zhang’s group, in collaboration with the Rockefeller University’s Luciano Marraffini, and independently George Church’s group, demonstrated that the CRISPR-Cas9 tool could effectively edit mammalian DNA. “That changed the world,” says Barrangou. Indeed, around the world researchers seized this simple, programmable gene-editing

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wounds and resubmitted to another journal… and another. Three more journals, including the Proceedings of the National Academy of Sciences (PNAS), all passed on CRISPR. Each delay increased the chances he might get scooped. Finally, in October 2004, Mojica submitted his manuscript to a lesser known journal specializing in evolution

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satisfying professional moment in my entire life.” * * * Mere weeks after Mojica began his publication odyssey,16, 17 Gilles Vergnaud in Paris submitted his own CRISPR story, and experienced similar frustrations. With concerns growing about Saddam Hussein’s use of biological weapons, Vergnaud, working for the French Ministry of Defense, was

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a poster presented by Alexander Bolotin. The poster mentioned a repetitive DNA motif called “SPIDR” (spaced interspersed direct repeats), which would later be renamed CRISPR. “We have identified a region with repeats that is very useful for strain identification,” Bolotin stated. Horvath was so intrigued that he snuck a photograph

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science award, the Spinoza Prize. “I don’t think John’s work will ever be forgotten,” says Koonin, the unofficial master record-keeper of CRISPR gene evolution.20 In Chicago, Erik Sontheimer and his Argentine postdoc, Luciano Marraffini, designed some clever experiments using Staphylococcus epidermis to settle another big question

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: does CRISPR-Cas target the viral RNA—mimicking RNAi—or DNA? Marraffini suspected it would be more efficient for bacteria to dispose of viral infections if they

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. Doudna replied, “We could use this for something better, like genome editing.” In June 2012, Jínek and Chyliński presented their discovery at the annual CRISPR conference, which had returned to Berkeley. Šikšnys presented his own unpublished results, which also demonstrated that Cas9 was a DNA-cutting enzyme. The overall impact

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2012, the publishing gods struck again. For five years, Šikšnys, the Lithuanian biochemist, had been collaborating with Horvath and Barrangou. After successfully transferring the CRISPR system from S. thermophilus to the lab-friendly E. coli, he surprisingly found that it could still defend against invading DNA, despite the two bacteria

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. Some politicians take pleasure in cherry-picking federal research grants (“sexual preferences in fruit flies,” etc.) as evidence of wasteful government spending. But the CRISPR gene-editing discovery and the scientific, medical, and economic bounty it has delivered, would not have happened but for public funding of unfashionable research conducted

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by diehard microbiologists, evolutionary biologists, biochemists, and structural biologists studying CRISPR purely for the thrill of discovery, not the lure of money or prizes. Fundamental and applied research are not “two spigots that can be operated

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) affiliated with both Harvard and MIT, anchored by a world-class genome center but venturing into cancer biology, neuroscience, cell biology, chemistry, and eventually CRISPR and genome editing. The philanthropists Eli Broad and his wife Edythe have committed $700 million to Lander’s institute, which the billionaire art collector calls

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awardee, Anthony Fauci, recognized for global health.) The Gairdner was the undoubted highlight of his career, recognition for a landmark study that fermented the CRISPR revolution. Doudna and Charpentier were deservedly recognized for developing the single-guide RNA technology—the tipping point as he calls it.12 “Single-guide RNA

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suggestion: “You need to leave your job!” he said. Charpentier partnered with Novak and Foy to create Inception Genomics in November 2013, which later became CRISPR Therapeutics. They initially selected Basel, Switzerland, as their pharma-friendly headquarters before relocating to Kendall Square for closer access to investors and talent. (They

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application. In January 2009, Sontheimer submitted a five-year, $1.8 million grant application to the NIH, entitled “RNA-Directed DNA Targeting in Eukaryotic Cells.” “CRISPR interference could provide unique capabilities, if it can be ported to eukaryotic cells,” Sontheimer wrote. “It could be easily programmed (and, when desired, reprogrammed)

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disruptive potential in biotechnology and medicine.”5 There were parallels to RNA interference, the technology codiscovered by the Nobel laureate next door, Craig Mello. But “CRISPR interference” was exciting because of the sequence specificity conferred by the twenty-four- to forty-eight-base spacers. Sontheimer and Marraffini’s discovery of “

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RNA-directed, DNA-targeting machinery in bacteria” suggested a route toward a “reprogrammable genome targeting system in eukaryotic cells.” Sontheimer’s plan was to port CRISPR into eukaryotic cells and test its ability to target specific genes. He would start small, working in yeast, then progress to Drosophila, and eventually mammalian

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Broad files first patent (’527) 2013 March 15 CVC files patent application (’859) 2014 April 15 Broad awarded ’527 patent July 7 Rockefeller files CRISPR patent 2015 April 13 CVC files “suggestion of interference” 2016 January 11 PTO declares an interference December 6 PTAB interference oral argument 2017 February 15

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.24 In January 2015, Doudna hosted a small retreat in Napa, California, where some fifteen invited experts, all Americans, discussed the potential misuses of CRISPR, including the prospect of engineering permanent, heritable fixes into human embryos. The guests included Asilomar veterans and Nobel laureates David Baltimore and Paul Berg, bioethicist

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Hidden Dragon” territory. After excelling at Peking University, Yang moved to Boston in 2008, working with Prashant Mali on the Church lab’s proof of CRISPR gene editing in human cells. Church was soon contacted by physicians at Massachusetts General Hospital (MGH) about improving the prospects of xenotransplantation patients. eGenesis is

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to reduce the mosquito population, including the sterile insect technique and the introduction of a natural bacterial predator, Wolbachia. Potentially the most effective technology involves CRISPR. It is also the most dangerous. * * * Eradicating diseases like Lyme disease, dengue fever, and especially malaria is a grand challenge on a global scale.

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: “illogical,” “absurd,” and “catastrophic” were representative reviews. Lynas said the ruling was “like saying doctors can use [a] blunderbuss but not [a] scalpel.” Placing CRISPR and GMOs in the same bucket was like “the Catholic Church classifying ducks as fish,” lamented Ewan Birney, a prominent British geneticist. Clive Brown, the

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to prime editing was extraordinary, even overshadowing Google’s claim of “quantum supremacy” published the same week. Commentators and journalists gushed about this gorgeous new “CRISPR 3.0” technology. The breakthrough even caught Elon Musk’s attention, who retweeted a New Scientist story. Urnov was much in demand, obligingly dashing

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editing technology. I could mention Homology Medicines, which is patching in a full gene delivered by a virus to genomic targets to treat phenylketonuria without CRISPR. Or an Israeli start-up called TargetGene Biotechnologies, which modestly claims it is developing “the world’s best therapeutic genome editing platform.” Or Tessera

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or person has ever given informed consent over the circumstances of their conception or the mash-up of genetic material that accompanied fertilization. Long before CRISPR babies, some argued that engineering genetic enhancements for cognitive or musical talent or athletic ability would steer such children toward a particular destiny, depriving

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spearheading hyper-personalized medicine. Encouraging, but each of these personalized drugs requires about $1–2 million at a minimum. * * * Like many researchers in the CRISPR spotlight, Jennifer Doudna receives regular emails from patients and their family members, desperately looking for hope. One message (shared publicly by Urnov) was written by

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to guanine (via uridine). The adenine base editor (ABE) catalyzes the transition of adenine to thymine (via inosine). Pope Francis urges caution in applying CRISPR during an address at the Vatican in April 2018. Courtesy of the Cura Foundation. Senator Elizabeth Warren quizzes former Editas CEO Katrine Bosley and Stanford

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, https://hilo.hawaii.edu/news/stories/2018/09/19/genome-editing-pioneer-and-hilo-high-graduate-jennifer-doudna-speaks-at-uh-hilo-about-her-discovery-crispr-technology/. 9. Katie Hasson, “Senate HELP Committee holds hearing on gene editing technology,” Center for Genetics and Society, November 15, 2017, https://www.

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-light-years-of-viruses/. 15. S. Klompe and S. H. Sternberg, “Harnessing A Billion Years of Experimentation: The Ongoing Exploration and Exploitation of CRISPR-Cas Immune Systems,” CRISPR Journal 1, (2018): 141-158. 16. Fyodor Urnov in Human Nature (2019), https://wondercollaborative.org/human-nature-documentary-film/. 17. CSHL Leading Strand

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and bacteria,” FEBS Journal 283, (2016): 3162–3169, https://febs.onlinelibrary.wiley.com/doi/full/10.1111/febs.13766. 18. C. Pourcel et al., “CRISPR elements in Yersinia pestis acquire new repeats by preferential uptake of bacteriophage DNA, and provide additional tools for evolutionary studies,” Microbiology 151, (2005): 653–663

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, https://mic.microbiologyresearch.org/content/journal/micro/10.1099/mic.0.27437-0. 19. A. Bolotin et al., “Clustered regularly interspaced short palindrome repeats (CRISPRs) have spacers of extrachromosomal origin,” Microbiology 151, (2005): 2551–2661. 20. Philippe Horvath, interview, Vilnius, Lithuania, June 21, 2018. 21. K. Davies and R.

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30, (2012): 836–868, https://www.nature.com/articles/nbt.2357. 12. Rodolphe Barrangou, interview, Victoria, Canada, February 21, 2019. 13. D. Carroll, “A CRISPR Approach to Gene Targeting,” Molecular Therapy 20, (2012): 1656–1660, https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(16)32156-6

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amaurosis type 10,” Nature Medicine 25, (2019): 229–233, https://www.nature.com/articles/s41591-018-0327-9. 18. Marilynn Marchione, “Doctors try 1st CRISPR editing in the body for blindness,” AP News, March 4, 2020, https://apnews.com/17fcd6ae57d39d06b72ca40fe7cee461. 19. Rob Wright, “A CEO’s most formative leadership experience

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Marchione, “AP Exclusive: US scientists try 1st gene editing in the body,” AP News, November 15, 2017, https://apnews.com/4ae98919b52e43d8a8960e0e260feb0a. 2. Aging Reversed, “AP—CRISPR babies in China,” YouTube video, 2:50, November 26, 2018, https://youtu.be/qUiNG1iW4Ww. 3. Jill Adams, “A conversation with Marilynn Marchione,” Open Notebook,

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,” YouTube video, 4:43, last viewed June 30, 2020, https://www.youtube.com/watch?v=th0vnOmFltc. 19. Living MacTavish, “In Conversation With Scientist and CRISPR Pioneer Jennifer Doudna,” YouTube video, 47:30, November 30, 2017, https://www.youtube.com/watch?v=YVoPRSPEpvU&list=PLdT7Y4C6bsoSUdt2PB1NQlVQgKULTARXk&index=47&t=1898s. 20. Paul

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, 2018, https://thebulletin.org/2018/12/brave-new-world-with-chinese-characteristics/. 4. J. He and M. W. Deem, “Heterogeneous diversity of spacers within CRISPR (clustered regularly interspaced short palindromic repeats),” Physical Review Letters 105, (2010): 128102, https://journals.aps.org/prl/abstract/10.1103/PhysRevLett.105.128102#fulltext. 5

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.be/POIeIILDo7k. 30. Sandy Macrae, “Workshop on Genome Editing,” National Academy of Sciences, Washington, DC, August 2019. 31. David Cyranoski, “Russian biologist plans more CRISPR-edited babies,” Nature, June 10, 2019, https://www.nature.com/articles/d41586-019-01770-x. 32. “Expert reaction to New Scientist exclusive reporting that five

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scientists in check,” STAT, February 23, 2017, https://www.statnews.com/2017/02/23/bioethics-harvard-george-church/. 36. K. Kyrou et al., “A CRISPR–Cas9 gene drive targeting doublesex causes complete population suppression in caged Anopheles gambiae mosquitoes,” Nature Biotechnology 36, (2018): 1062–1066, https://www.nature.com/articles

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has the potential to correct almost all disease-causing DNA glitches, scientists report,” STAT, October 21, 2019, https://www.statnews.com/2019/10/21/new-crispr-tool-has-potential-to-correct-most-disease-causing-dna-glitches/. 27. Julianna LeMieux, “Genome Editing Heads to Primetime,” Genetic Engineering & Biotechnology News, October 21,

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Henner, Marilu, 343 Hereditary persistence of fetal hemoglobin (HPFH), 156–157 Heritable genome editing, xvii, 228, 257, 362. See also Genome editing; Germline “Heroes of CRISPR,” 92, 272 Herper, Matthew, 89 Herrick, James, 154 Hershey, Alfred, 109 High, Katherine, 149 Highly superior autobiographical memory (HSAM), 343 HIV, 5, 105, 116

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, 45, 69 Verinata Health, 208, 209 Verrilli, Donald, 186–187 Vertex Pharmaceuticals, 138, 169, 177 Verve Therapeutics, 331, 345 Vibrio cholera, 102 “Villain of CRISPR, The,” 93 Villarreal, Evelyn, 159 Villarreal, Josephine, 159 Vilnius Institute of Biotechnology, 54 Viral code, storing, 23 Viruses adeno-associated viruses, 99, 121, 145–146

A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution

by Jennifer A. Doudna and Samuel H. Sternberg  · 15 Mar 2017

Harcourt, 2017. | Includes bibliographical references and index. Identifiers: LCCN 2016058472 (print) | LCCN 2016059585 (ebook) | ISBN 9780544716940 (hardcover) | ISBN 9780544716964 (ebook) Subjects: | MESH: Gene Editing—history | CRISPR-Cas Systems | Genetic Code | Genetic Research—history | United States Classification: LCC QH440 (print) | LCC QH440 (ebook) | NLM QU 11 AA1 | DDC 576.5072—dc23 LC

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the genetic code that defines every species on the planet, including our own. And with the newest and arguably most effective genetic engineering tool, CRISPR-Cas9 (CRISPR for short), the genome—an organism’s entire DNA content, including all its genes—has become almost as editable as a simple piece of text

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latter supported by more than a billion dollars from investors and venture capital firms. Spurring the field, academic researchers and nonprofit groups are providing inexpensive, CRISPR-related tools to scientists around the world so that research can proceed unimpeded. But scientific progress requires more than research, investment, and innovation; public involvement

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this kind of precision and uniformity, where every repetition was truly identical and always separated from its neighbor by a similarly sized, random spacer sequence. CRISPR inside a bacterial cell Curious to learn more about these strange regions of bacterial DNA, I asked Jill about their biological function and was disappointed

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stack of papers and excitedly summarized the results. Working independently, three research laboratories, including the one headed by Mojica, had found that many of the CRISPR spacers—those snippets of DNA sandwiched between the repeating sequences—were perfect matches with the DNA of known bacterial viruses. Even more intriguing, there seemed

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two researchers at Northwestern University, Luciano Marraffini and his mentor Erik Sontheimer, a colleague I knew from his student days at Yale, figured out that CRISPR RNA could, indeed, direct the destruction of DNA. Working with yet another microorganism called Staphylococcus epidermidis, a relatively benign human skin bacterium (but a close

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someday be used to improve human health. In their experiments published in our 2012 Science article, Martin and Krzysztof had demonstrated something groundbreaking: that a CRISPR-associated protein called Cas9, isolated from flesh-eating bacteria, worked with two molecules of RNA to target matching twenty-letter DNA sequences and cut them

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as limb regeneration in Mexican salamanders, aging in killifish, and skeletal development in crustaceans. I love the notes and pictures colleagues send me describing their CRISPR experiments—the beautiful butterfly-wing patterns whose genetic underpinnings they’ve uncovered, or the infectious yeast whose ability to invade human tissues they’ve dissected

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including natural mutagenesis, induced mutagenesis using x-rays or chemicals, and hybridization between different plant species (which floods the genome with thousands of new genes)—CRISPR and its kindred technologies give scientists a level of control over the genome that is unparalleled. The possibilities of this technology for agriculture were highlighted

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an outcome threatened by the spread of a devastating soil fungus. And elsewhere, researchers are even toying with the possibility of inserting the entire bacterial CRISPR system, reprogrammed to slice up plant viruses, into crops, providing them with a completely new antiviral immune system. I’m particularly intrigued by opportunities to

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slowly brewing around gene-edited organisms, however. Some of the first activist-led protests over the new technology took place in the spring of 2016. CRISPR researchers have even been threatened by activists who had previously focused their attention on GMOs. One of the biggest challenges facing agricultural companies, farmers, consumers

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in humans, at least one other case has since been reported, this one in a Michigan family. Double-muscled animals, both natural and created with CRISPR Researchers are now investigating whether replicating this condition with deliberate mutations—that is, stimulating muscle growth by inactivating the myostatin gene—may be a viable

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transgenes, producers hope that the pigs will be regulated no differently than animals like Belgian Blue cattle, which developed double muscling through natural mutations. Since CRISPR makes it easy to edit multiple genes, numerous new traits can be introduced simultaneously. For example, Chinese scientists working with goats targeted the myostatin gene

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hornless cattle might have been produced by years of conventional breeding. Gene editing merely allowed the same outcome to be achieved much more efficiently. If CRISPR and related technologies can eliminate inhumane practices like dehorning, reduce antibiotic usage, and protect livestock from deadly infections, can we afford not to use them

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genetic model—an animal whose condition closely mimics that of the diseased patient group in terms of both physical manifestations and the underlying genetic causes. CRISPR offers an effective, streamlined approach to accomplish this. The preferred mammalian model organism for biomedical research since the early twentieth century has been the common

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There are numerous benefits to extracting the drugs from transgenic animals rather than from cultured cells, including higher yields, easier scale-up, and lower costs. CRISPR promises to further improve farmaceutical production by giving scientists far better genetic control over creation of the transgenic animals in the first place. For example

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eligible to receive a transplant. The shortage of donor organs is the biggest cause of this ongoing tragedy. Xenotransplantation using humanized pigs New technologies including CRISPR provide a way to generate pigs with organs suitable for human transplant. Previous advances focused on transferring human genes into the pig genome so that

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independently of the California scientists, a British team of researchers—among them Austin Burt, the biologist who pioneered the gene drive concept—created highly transmissive CRISPR gene drives that spread genes for female sterility. Since the sterility trait was recessive, the genes would rapidly spread through the population, increasing in frequency

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cull entire populations by hindering reproduction. If sustained in wild-mosquito populations, it could eventually lead to outright extermination of an entire mosquito species. Using CRISPR to build gene-drive mosquitoes It’s not the first time that scientists have turned to genetic engineering to reduce insect populations. A common practice

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as various metabolic disorders affecting the liver. Meanwhile, working in cultured human cells that were often derived from patient tissue samples, hundreds of researchers used CRISPR to repair an ever-expanding number of DNA mutations associated with some of the most devastating genetic diseases out there, everything from sickle cell disease

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use viruses at all. Building on advances in nanotechnology—the science of fabricating submicroscopic structures—researchers are exploring the use of lipid nanoparticles to ferry CRISPR throughout the body. Resistant to degradation and easy to manufacture, these delivery vehicles also have the benefit of releasing the Cas9 protein and its guide

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in mice—ended up a resounding success and a major endorsement for using gene editing to further immunotherapy. Thanks to Layla’s case and others, CRISPR-based therapeutics companies have already struck major deals with cancer immunotherapy companies to combine their respective platforms. Editas Medicine has an exclusive multimillion-dollar license

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thus far, a quick survey of the published scientific literature reveals a growing list of diseases for which potential genetic cures have been developed with CRISPR: achondroplasia (dwarfism), chronic granulomatous disease, Alzheimer’s disease, congenital hearing loss, amyotrophic lateral sclerosis (ALS), high cholesterol, diabetes, Tay-Sachs, skin disorders, fragile X syndrome

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UCLA conference, its participants were wrestling with many of the same concerns about germline modification that have resurfaced in recent years with the advent of CRISPR, issues such as consent, inequality, access, and unintended consequences for future generations. Like many concerned scientists today, these researchers grappled with the thorny question

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Regulators have nevertheless greenlighted this reproductive therapy. Reading about these cases, I had to ask myself: Would regulators and researchers be just as comfortable using CRISPR to make heritable changes to the human genome, given that its power is so much greater than these earlier technologies? When fertility doctors eventually realize

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all, gave formal presentations on gene therapy and germline enhancement, on existing regulations that governed genetically modified products, and on the nitty-gritty details of CRISPR. Even more interesting than these presentations, in my opinion, were the group’s open-table deliberations about the future of gene editing. These conversations were

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editing technologies, their potential risks and rewards, and their associated ethical, social, and legal implications. We called on researchers to continue testing and developing the CRISPR technology in cultured human cells and in nonhuman animal models so that its safety profile could be better understood in advance of any clinical applications

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lipoprotein cholesterol (the “bad” cholesterol), making the gene one of the most promising pharmaceutical targets to prevent heart disease—the leading cause of death worldwide. CRISPR could be programmed to tweak this gene and save unborn people from high cholesterol. Would this qualify as therapeutic germline editing or enhancement gene editing

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bans on federal funding for germline editing. There’s also a risk that overly restrictive policies in some countries will encourage what might be called CRISPR tourism in others. Patients with means could travel overseas to jurisdictions where regulations are more forgiving or absent altogether. Medical tourists have already spent millions

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right balance between regulation and freedom. Scientific experts should work to create a set of standardized, agreed-upon guidelines that specify the safest methods of CRISPR delivery, prioritize disease-causing genes for research, and set quality-control standards to evaluate gene-editing interventions. And government officials—especially in the United States

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of Regularly Spaced Prokaryotic Repeats Derive from Foreign Genetic Elements,” Journal of Molecular Evolution 60 (2005): 174–82; C. Pourcel, G. Salvignol, and G. Vergnaud, “CRISPR Elements in Yersinia pestis Acquire New Repeats by Prefer­ential Uptake of Bacteriophage DNA, and Provide Additional Tools for Evolutionary Studies,” Microbiology151 (2005): 653–63

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; A. Bolotin et al., “Clustered Regularly Interspaced Short Palindrome Repeats (CRISPRs) Have Spacers of Extrachromosomal Origin,” Microbiology 151 (2005): 2551–61. Jill’s own pioneering research: A. F. Andersson and J. F. Banfield, “Virus Population

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et al., “Identification of Genes That Are Associated with DNA Repeats in Prokaryotes,” Molecular Microbiology 43 (2002): 1565–75. the first bacterium in which a CRISPR sequence had been identified: Y. Ishino et al., “Nucleotide Sequence of the Iap Gene, Responsible for Alkaline Phosphatase Isozyme Conversion in Escherichia coli, and Identification

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by-doing#/. editing the yeast genome to make new flavors of beer: E. Callaway, “Tapping Genetics for Better Beer,” Nature535 (2016): 484–86. 5. THE CRISPR MENAGERIE discovered gene mutations that made the plant resistant to a pernicious fungus: P. Piffanelli et al., “A Barley Cultivation-Associated Polymorphism Conveys Resistance to

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3, 2016. “a very large reptile that looks at least somewhat like the European or Asian dragon”: R. A. Charo and H. T. Greely, “CRISPR Critters and CRISPR Cracks,”American Journal of Bioethics 15 (2015): 11–17. This strategy is being undertaken in Europe to bring back the aurochs: B. Switek, “How

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annual meeting for the American Society of Hematology, Orlando, Florida, December 5–8, 2015. inject human patients with cells that had been modified using CRISPR: D. Cyranoski, “CRISPR Gene-Editing Tested in a Person for the First Time,” Nature News, November 15, 2016. the Cas9 enzyme would in some cases still cut

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1483–89. Every person experiences roughly one million mutations throughout the body: M. Porteus, “Therapeutic Genome Editing of Hematopoietic Cells,” Presentation at Inserm Workshop 239, CRISPR-Cas9: Breakthroughs and Challenges, Bor­deaux, France, April 6–8, 2016. every single letter of the genome will have been mutated at least once: M

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light chain A (CLTA) gene, 93 cloning, 144–45, 191–92, 196 CLTA (clathrin light chain A) gene, 93 clustered regularly interspaced short palindromic repeats (CRISPR). See CRISPR codon, 102 collaboration, 61, 70, 73, 75, 77, 84, 242 Collins, Francis, 217, 227 communication, 197 IGI Forum on Bioethics, 206–10 lack of

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191, 201, 205, 208–40 preimplantation genetic diagnosis, 195 See also ethics Corn, Jacob, 206 correction, spontaneous, 5–7 Crichton, Michael, 145 Crick, Francis, 10 CRISPR (clustered regularly interspaced short palindromic repeats), 34, 42 ability to target many genes at once, 173–74 accuracy, 222–24 as antiviral defense mechanism, 50

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Modification,” 211–12 publication and ramifications of work, xvi–xviii Sullenger and, 21–22 TV interview, 38–39, 155 Yale, faculty member, 20 See also CRISPR (clustered regularly interspaced short palindromic repeats); Sternberg, Sam Drubin, David, 93 drugs, from transgenic animals, 139–40 dual-use technology, 217 Duchenne muscular dystrophy (

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livestock, 128–37 LRP5 gene, 230 Lunshof, Jeantine, 143 M Makarova, Kira, 44, 68 Marraffini, Luciano, 59, 96 Martin, Steven, 207 medical tourism, 237 medicine CRISPR’s potential in, 154 drugs from transgenic animals, 139–40 See also diseases; public health; therapeutics Mello, Craig, 40 messenger RNA (mRNA), 102 mice, 97

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, 24–26 possibilities of, 155–58 in vivo gene editing, 161, 167–71 See also diseases; medicine threat assessment, 217–18 thymine, 9, 11 tourism, CRISPR, 237 tracrRNA, 78, 80, 82, 91 transcription, 11 transcription activator-like effectors (TALEs), 33–34 translation, 11 transplantation, 118, 140–42, 141 Triticum aestivum,

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the Molecular Biophysics and Integrated Bioimaging Division at the Lawrence Berkeley National Laboratory. She is internationally recognized as a leading expert on RNA-protein biochemistry, CRISPR biology, and genome engineering. She lives in the San Francisco Bay Area. SAMUEL H. STERNBERG, Ph.D., is a biochemist and author of numerous

The Code Breaker: Jennifer Doudna, Gene Editing, and the Future of the Human Race

by Walter Isaacson  · 9 Mar 2021  · 700pp  · 160,604 words

,” one of the participants assured her. “Nobody’s got any travel plans.” * * * What none of the participants discussed was a longer-range prospect: using CRISPR to engineer inheritable edits in humans that would make our children, and all of our descendants, less vulnerable to virus infections. These genetic improvements could

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When he got home, he asked his wife what she thought of the name. “It sounds like a great name for a dog,” she said. “Crispr, Crispr, come here, pup!” He laughed and decided it would work. On November 21, 2001, the name was anointed in an email from Jansen in reply

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. “Steam engines led to the understanding of thermodynamics, not the other way round. Powered flight preceded almost all aerodynamics.”2 The colorful history of CRISPR provides another great tale about this symbiosis between basic and applied science. And it involves yogurt. Barrangou and Horvath As Doudna and her team began

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everyone, can change the world,” Banfield later noted. Among the first accomplishments was standardizing the lingo and names, including adopting a common designation for the CRISPR-associated proteins. Sylvain Moreau, one of the pioneer participants, called the July meeting “our scientific Christmas party.”7 Sontheimer and Marraffini The year of

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email that did not portend a happy new year: From: Feng Zhang Sent: Wednesday, January 02, 2013 7:36 PM To: Jennifer Doudna Subject: CRISPR Attachments: CRISPR manuscript.pdf Dear Dr. Doudna, Greetings from Boston and happy new year! I am an assistant professor at MIT and have been working on developing

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Intellia, because the Caribou team was launching it with the academic scientists I most liked and trusted and respected,” Doudna says. These included three great CRISPR pioneers, Rodolphe Barrangou, Erik Sontheimer, and Zhang’s former collaborator Luciano Marraffini. They were all brilliant but had an even more important trait: “They

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ethics story, which Jiankui and Ferrell titled “Draft Ethical Principles for Therapeutic Assisted Reproductive Technologies,” was intended for a new publication called the CRISPR Journal, edited by the CRISPR pioneer Rodolphe Barrangou and the science journalist Kevin Davies. In his draft, Jiankui listed five principles that should be followed when deciding whether

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is any microorganism that causes disease or infection. The most common are viruses, bacteria, fungi, and protozoa. Stanley Qi Nathan and Cameron Myhrvold CHAPTER 54 CRISPR Cures The development of vaccines—both the conventional sort and those employing RNA—would eventually help to beat back the coronavirus pandemic. But they are

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voice choking up a bit. “Rosalind is the godmother of gene editing.” Doudna’s talk began with a reminder of the natural connection between CRISPR and COVID. “CRISPR is a fabulous way that evolution has dealt with the problem of viral infection,” she said. “We can learn from it in this pandemic

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harbor. There you can find, on most summer evenings, conference attendees, researchers from nearby lab buildings, and the occasional groundskeeper or campus worker. During previous CRISPR conferences, it was filled with talk of impending discoveries, fanciful ideas, potential job openings, and high and low gossip. In 2020, the conference organizers

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traditionally been independent fiefdoms that fiercely guard their autonomy. Fighting the coronavirus required collaboration across disciplines. In that way, it resembled the effort to develop CRISPR, which involved microbe-hunters working with geneticists, structural biologists, biochemists, and computer geeks. It also resembled the way things operate in innovative businesses, where

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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

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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

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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

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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’

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Ridley, How Innovation Works (Harper Collins, 2020), 282. 3. Author’s interviews with Rodolphe Barrangou. 4. Rodolphe Barrangou and Philippe Horvath, “A Decade of Discovery: CRISPR Functions and Applications,” Nature Microbiology, June 5, 2017; Prashant Nair, “Interview with Rodolphe Barrangou,” PNAS, July 11, 2017; author’s interviews with Rodolphe Barrangou. 5

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. Author’s interviews with Rodolphe Barrangou. 6. Rodolphe Barrangou… Sylvain Moineau… Philippe Horvath, et al., “CRISPR Provides Acquired Resistance against Viruses in Prokaryotes,” Science, Mar. 23, 2007 (submitted Nov. 29, 2006; accepted Feb. 16, 2007). 7. Author’s interviews with Sylvain

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interview with Luciano Marraffini. 9. Author’s interview with Erik Sontheimer. 10. Author’s interviews with Erik Sontheimer, Luciano Marraffini; Luciano Marraffini and Erik Sontheimer, “CRISPR Interference Limits Horizontal Gene Transfer in Staphylococci by Targeting DNA,” Science, Dec. 19, 2008; Erik Sontheimer and Luciano Marraffini, “Target DNA Interference with crRNA,” U

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’s interview with Rachel Haurwitz. 3. Rachel Haurwitz, Martin Jinek, Blake Wiedenheft, Kaihong Zhou, and Jennifer Doudna, “Sequence- and Structure-Specific RNA Processing by a CRISPR Endonuclease,” Science, Sept. 10, 2010. 4. Samuel Sternberg… Ruben L. Gonzalez Jr., et al., “Translation Factors Direct Intrinsic Ribosome Dynamics during Translation Termination and

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Novak,” Refresh Berlin, May 24, 2016, Labiotech.eu. 5. Author’s interview with Emmanuelle Charpentier. 6. Elitza Deltcheva, Krzysztof Chylinski… Emmanuelle Charpentier, et al., “CRISPR RNA Maturation by Trans-encoded Small RNA and Host Factor RNase III,” Nature, Mar. 31, 2011. 7. Author’s interviews with Emmanuelle Charpentier, Jennifer Doudna

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of Health, Jan. 12, 2012. 6. Broad Opposition 3; UC reply 3. 7. Author’s interviews with Luciano Marraffini and Erik Sontheimer; Marraffini and Sontheimer, “CRISPR Interference Limits Horizontal Gene Transfer in Staphylococci by Targeting DNA”; Sontheimer and Marraffini, “Target DNA Interference with crRNA,” U.S. Provisional Patent Application; Kevin Davies

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, “Interview with Luciano Marraffini,” CRISPR Journal, Feb. 2020. 8. Author’s interviews with Luciano Marraffini and Feng Zhang; Zhang email to Marraffini, Jan. 2, 2012 (given to me by

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“Interview with Luciano Marraffini.” Chapter 25: Doudna Joins the Race 1. Author’s interviews with Martin Jinek and Jennifer Doudna. 2. Melissa Pandika, “Jennifer Doudna, CRISPR Code Killer,” Ozy, Jan. 7, 2014. 3. Author’s interviews with Jennifer Doudna and Martin Jinek. Chapter 26: Photo Finish 1. Author’s interviews with

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Junk Journalism,” The Atlantic, Jan. 22, 2013. 3. Author’s interview with Rodger Novak; Hemme, “Fireside Chat with Rodger Novak”; Jon Cohen, “Birth of CRISPR Inc.,” Science, Feb. 17, 2017; author’s interviews with Emmanuelle Charpentier. 4. Author’s interviews with Jennifer Doudna, George Church, and Emmanuelle Charpentier. 5. Author

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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

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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

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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

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et al., “Human Genome Editing: Scientific, Medical, and Ethical Considerations,” report of the National Academies of Sciences, Engineering, Medicine, 2017. 18. Françoise Baylis, Altered Inheritance: CRISPR and the Ethics of Human Genome Editing (Harvard, 2019); Jocelyn Kaiser, “U.S. Panel Gives Yellow Light to Human Embryo Editing,” Science, Feb. 14, 2017

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, “Human Gene Editing Morally Permissible, Says Ethics Study,” Financial Times, July 17, 2018; Donna Dickenson and Marcy Darnovsky, “Did a Permissive Scientific Culture Encourage the ‘CRISPR Babies’ Experiment?,” Nature Biotechnology, Mar. 15, 2019. 20. Consolidated Appropriations Act of 2016, Public Law 114-113, Section 749, Dec. 18, 2015; Francis Collins, “

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Atomic Scientists, Jan. 13, 2019; He Jiankui, “Draft Ethical Principles,” YouTube, Nov. 25, 2018, youtube.com/watch?v=MyNHpMoPkIg; Antonio Regalado, “Chinese Scientists Are Creating CRISPR Babies,” MIT Technology Review, Nov. 25, 2018; Marilynn Marchione, “Chinese Researcher Claims First Gene-Edited Babies,” AP, Nov. 26, 2018; Christina Larson, “Gene-Editing Chinese

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, Monkey, and Mouse Embryos,” Cold Spring Harbor Lab Symposium, July 29, 2017, youtube.com/watch?v=llxNRGMxyCc&t=3s; Regalado, “Chinese Scientists Are Creating CRISPR Babies.” 16. Medical Ethics Approval Application Form, HarMoniCare Shenzhen Women’s and Children’s Hospital, March 7, 2017, theregreview.org/wp-content/uploads/2019/05

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“Could Anyone Have Stopped Gene-Edited Babies Experiment?”; Marchione, “Chinese Researcher Claims First Gene-Edited Babies”; Jane Qiu, “American Scientist Played More Active Role in ‘CRISPR Babies’ Project Than Previously Known,” Stat, Jan. 31, 2019; Todd Ackerman, “Lawyers Say Rice Professor Not Involved in Controversial Gene-Edited Babies Research,” Houston Chronicle

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New World Revisited (Harper, 1958), 120. 8. Aldous Huxley, Island (Harper, 1962), 232; Derek So, “The Use and Misuse of Brave New World in the CRISPR Debate,” CRISPR Journal, Oct. 2019. 9. Nathaniel Comfort, “Can We Cure Genetic Diseases without Slipping into Eugenics?,” The Nation, Aug. 3, 2015; Nathaniel Comfort, The Science

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-Editing Tools,” GeneCopoeia.com. 3. Author’s interviews with Jennifer Hamilton. Chapter 46: Watson Revisited 1. Author’s interviews with James Watson, Jennifer Doudna; “The CRISPR/Cas Revolution,” Cold Spring Harbor Laboratory meeting, Sept. 24–27, 2015. 2. David Dugan, producer, DNA, documentary, Windfall Films for WNET/PBS and BBC4,

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relaunched in January 2017 as the Innovative Genomics Institute. 2. Author’s interview with Dave Savage; Benjamin Oakes… Jennifer Doudna, David Savage, et al., “CRISPR-Cas9 Circular Permutants as Programmable Scaffolds for Genome Modification,” Cell, Jan 10, 2019. 3. Author’s interviews with Dave Savage, Gavin Knott, and Jennifer Doudna

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Unleashes Indiscriminate Single-Stranded DNase Activity,” Science, Apr. 27, 2018 (received Nov. 29, 2017; accepted Feb. 5, 2018; published online Feb. 15); John Carroll, “CRISPR Legend Jennifer Doudna Helps Some Recent College Grads Launch a Diagnostics Up-start,” Endpoints, Apr. 26, 2018. 3. Sergey Shmakov, Omar Abudayyeh, Kira S. Makarova

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… Konstantin Severinov, Feng Zhang, and Eugene V. Koonin, “Discovery and Functional Characterization of Diverse Class 2 CRISPR-Cas Systems,” Molecular Cell, Nov. 5, 2015 (published online Oct. 22, 2015); Omar Abudayyeh, Jonathan Gootenberg… Eric Lander, Eugene Koonin, and Feng Zhang, “C2c2

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Race for a Coronavirus Vaccine,” New York Times, Nov. 21, 2020; author’s interviews with Noubar Afeyan, Moncef Slaoui, Philip Dormitzer, Christine Heenan. Chapter 54: CRISPR Cures 1. David Dorward… and Christopher Lucas, “Tissue-Specific Tolerance in Fatal COVID-19,” medRxiv, July 2, 2020; Bicheng Zhag… and Jun Wan, “Clinical

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. 3. Author’s interview with Cameron Myhrvold. 4. Jonathan Gootenberg, Omar Abudayyeh… Cameron Myhrvold… Eugene Koonin… Pardis Sabeti… and Feng Zhang, “Nucleic Acid Detection with CRISPR-Cas13a/C2c2,” Science, Apr. 28, 2017. 5. Cameron Myhrvold, Catherine Freije, Jonathan Gootenberg, Omar Abudayyeh… Feng Zhang, and Pardis Sabeti, “Field-Deployable Viral Diagnostics

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interview with Cameron Myhrvold. 7. Cameron Myhrvold to Pardis Sabeti, Dec. 22, 2016. 8. Defense Advanced Research Projects Agency (DARPA) grant D18AC00006. 9. Susanna Hamilton, “CRISPR-Cas13 Developed as Combination Antiviral and Diagnostic System,” Broad Communications, Oct. 11, 2019. 10. Catherine Freije, Cameron Myhrvold… Omar Abudayyeh, Jonathan Gootenberg… Feng Zhang, and

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, Dec. 5, 2019 (received Apr. 16, 2019; revised July 18, 2019; accepted Sept. 6, 2019; published online Oct. 10, 2019); Tanya Lewis, “Scientists Program CRISPR to Fight Viruses in Human Cells,” Scientific American, Oct. 23, 2019. 11. Cheri Ackerman, Cameron Myhrvold… and Pardis C. Sabeti, “Massively Multiplexed Nucleic Acid Detection

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Biosciences (QB3), 116 Caltech, 270 Cambridge University Cavendish Laboratory, 20–23, 26 Camus, Albert, 399 cancer, xviii, 100, 177, 259, 339, 365, 441, 442 CRISPR and, xviii, 249–51 Canseco, José, 349 Carey, Mariah, 352 Caribou Biosciences, 113–18, 203, 207–8, 213 Intellia Therapeutics, 213 CARMEN, 453, 460 Carroll

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diseases, fend off viruses, and enhance our children”-- Provided by publisher. Identifiers: LCCN 2020043552 | ISBN 9781982115852 (hardcover) | ISBN 9781982115876 (ebook) Subjects: LCSH: Doudna, Jennifer A. | CRISPR (Genetics) | Gene editing. Classification: LCC QH440 .I83 2021 | DDC 576.5--dc23 LC record available at https://lccn.loc.gov/2020043552 ISBN 978-1-9821

As Gods: A Moral History of the Genetic Age

by Matthew Cobb  · 15 Nov 2022  · 772pp  · 150,109 words

the real possibility of catastrophe: • In 2018 we stepped into the brave new world of heritable human genome editing when Chinese researcher He Jianqui used CRISPR gene editing in a botched experiment that mutated three healthy embryos, with unknown consequences for the resulting children. Despite a global outcry, there is

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including Nobel Prize-winning leaders of the field, have rejected this approach. This time around, there is no consensus. Despite the widespread revulsion at the CRISPR babies experiment, there is no guarantee that it will not be repeated tomorrow. These examples show the singularity of genetic engineering in the history of

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the development of GM crops and gene therapy, massive advances in our scientific understanding of the whole of biology and, ultimately, the current excitement over CRISPR gene editing. The techniques used during this revolution have changed – Berg’s pioneering but primitive genetic engineering and today’s gene editing are radically different

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).102 Although Randy Lewis of Utah State University has continued the spider-goat project with financial backing from the US Navy, it seems likely that CRISPR-based recombinant DNA production of spider silk in silkworms, which have been used for millennia in silk production, will prove more successful, if less

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unusual degree of care will be needed with novel applications’. Even more perceptively, the report contained a warning to twenty-first-century advocates of using CRISPR on humans: If genetically engineered changes ever become relatively easy to make, there may be a tendency to identify what are in fact social

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cutting it, might be involved in DNA repair in these microbes.20 Email from Ruud Jansen to Francisco Mojica, November 2001, approving the CRISPR acronym. As the CRISPR acronym indicates, these repeated sequences tended to be clustered in the genome, were vaguely palindromic and were regularly interspaced with other stuff. Initially

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by Philippe Horvath and Rodolphe Barrangou (Danisco was interested in the phenomenon because the bacteria involved in producing yoghurt were repeatedly attacked by bacteriophages, and CRISPR might be a way of protecting them). They showed that after infection with a bacteriophage, bacterial colonies acquired new ‘spacer’ DNA from the virus;

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Fire had recently won the Nobel Prize in Physiology or Medicine for their discovery of the influential RNA interference technique, which may have skewed assumptions.) CRISPR was beginning to attract attention – there were publications in leading journals, the sequences were found throughout the microbial tree of life, which suggested that

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understanding of the process. Finally, a group led by Virginius Šikšnys of Vilnius University in Lithuania, in collaboration with Horvath and Barrangou, transferred the CRISPR system from one species of bacteria to another and suggested that one Cas enzyme, Cas9, was the nuclease that cut the DNA molecule. It was

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RNA – thereby making programming the system even more straightforward. This reveals a second difference between the two articles. Although both papers highlighted the potential of CRISPR, Doudna and Charpentier were much more clear-sighted because their additional step using a single guide RNA molecule allowed them to fully grasp the implications

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Science website at the beginning of January 2013.38 Feng Zhang, a young researcher from the Broad (rhymes with ‘road’) Institute had become interested in CRISPR in 2011 (somewhat alarmingly, Zhang was inspired to work in genetic engineering after watching Jurassic Park as a teenager39). With his colleagues, Zhang showed

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, was set to transform science and medicine. ✴ In the year following the breakthrough papers of 2012 there were over 250 scientific articles published on CRISPR as researchers rushed to show how it could have a massive impact on fundamental, applied and medical science – it was used to create mutant zebrafish

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those on those gene editing has-beens, TALENs and zinc finger nucleases, increasing exponentially and passing 7,000 papers in 2021. Exactly as hoped, CRISPR proved a game-changer, allowing genetic manipulation of any organism. The precise details of the system continue to evolve as researchers explore the huge range

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the Nobel Prize. Although it is generally invidious to give scientific prizes to a small number of people, and particularly so in the case of CRISPR, given how many scientists made significant contributions, the scientific community appeared to be pleased at the award, partly because women have so rarely been recognised

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embryos is impossible; you would have to sequence the genome of every cell in the embryo, which would involve destroying it. Checking the efficacy of CRISPR in somatic cells, manipulated outside the body, is relatively straightforward – those cells are not unique and precious, and some can be sacrificed to measure

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areas are already destined to do different things, and above all the cell is in motion and, compared to the tiny molecules involved in CRISPR, vast. The CRISPR components have to rapidly find the chromosomes, get access to the bases which are on the inside of the double helix and then screen

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was clear: ‘Don’t Edit the Human Germ Line’. Lanphier and Urnov’s hostility to germline modification was focused on the problems associated with using CRISPR in humans. They swept aside the ethical arguments that had preoccupied the field for decades, highlighting the immediate issue – the safety and reliability of

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the efficiency was alarmingly low for a potentially clinical procedure. Of eighty-six injected embryos, seventy-one survived the process, but only twenty-eight showed CRISPR cleavage of the target gene. Furthermore, many of these embryos were mosaic, there were off-target effects and sometimes new mutations were mistakenly introduced,

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genetic engineering had finally dawned. In May, Nature Biotechnology solicited the views of leading figures in the world of gene editing, under the grandiose title ‘CRISPR Germline Editing – The Community Speaks’.14 i Most of the contributors agreed with Craig Venter, who idly blended technofuturism with Nietzsche: I think that

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we as a society want to use this capability?27 The most straightforward discussions at the Summit revolved around somatic cell modification – gene therapy using CRISPR or other editing approaches. These techniques raised few ethical or safety issues, although even here there was the risk that the editing might not

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pointed out, in contemporary debates over germline gene editing the contributions of non-scientists needed to take centre stage: To produce politically legitimate policymaking for CRISPR/Cas9, then, citizens must be engaged and treated as equals in the discussion.… rather than serving as a model for governing emerging science and

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Asilomar, like the scientists who invoked its legacy, were missing the fundamental point. They all seemed to assume that the gritty safety issues of using CRISPR had been overcome, or could easily be so, and that the fundamental questions relating to the technology were ethical, political or sociological. But whatever

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verbs such as ‘construct’, ‘create’, ‘link’ and ‘join’ were employed, portraying researchers as the decisive component in the scientific process. In the 2015 Napa letter, CRISPR was often the subject of a sentence, suggesting that it was an autonomous agent of change rather than something that is under our control and

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we will orient toward this technology as a tool under the control of scientists and science regulators’. She concluded bleakly: ‘scientists are powerless in CRISPR’s world, carried along for the ride by a family of technologies that are revolutionising biomedicine’.36 This is a slight exaggeration and involves reading

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to gene editing – the same thing is done with nuclear power or smartphones. But Ceccareilli was right to highlight that the phraseology employed around CRISPR often gives the impression of an inexorable process, with the result that scientists are conveniently no longer responsible for the consequences of their experiments. Conceiving

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. Four months earlier, Doudna had argued that a complete ban on germline engineering was impractical ‘given the widespread accessibility and ease of use of CRISPR–Cas9’.39 iii This feeling of inevitability was reinforced by an apparent breakthrough paper, which appeared in Nature in August 2017.40 This study was

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2018, in a report from the influential UK Nuffield Council on Bioethics. First, there was a large dose of optimism: ‘it is likely that different CRISPR-Cas9 technologies will be clinically safe in the foreseeable future’. ‘Safe’ was not defined. Then, with suitable bet-hedging about genome editing only being

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some commentators, risk could even be argued away. In August 2018 an editorial in Nature Medicine highlighted the need to study off-target effects in CRISPR but also emphasised that ‘a certain degree of risk is embedded in many promising and successful medical therapies’. The journal suggested that an acceptable

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received, while one of the main commentators on Twitter, Sean Ryder of the University of Massachusetts Medical School, published a scathing article in the CRISPR Journal.56 Subsequent analysis and discussion of both the science and the ethics of the affair confirmed and expanded this critique, in particular some brilliant

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an experiment gone wrong’. Musunuru says he let out a guttural scream when he realised that He Jiankui had implanted mosaic embryos. Musunuru, K., The CRISPR Generation: The Story of the World’s First Gene-Edited Babies (2019). – THIRTEEN – AFTERMATH As the news of He Jiankui’s dreadful experiment echoed

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term, one which downplayed the apparent simplicity of changing genetic sequences. These difficulties had been noted in 2015, when a group of researchers explored the CRISPR metaphors used in newspapers and popular science publications and concluded that two of the main terms – ‘editing’ and ‘targeting’ – were misleading: We see a

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the foreseeable future. Not even that is accepted by everyone. As Jennifer Doudna has argued from the outset, part of the problem of regulating CRISPR lies in its relative ease of use which means unprincipled researchers can simply ignore and evade regulation. Although editing embryos requires complex IVF facilities, which

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germline.33 There is one gang of fantasists who mix cryptocurrency funding and transhumanist nonsense in a toxic, nauseating nightmare, claiming that they will use CRISPR germline editing to produce babies who will live to be ‘super-centenarians’ or will ‘grow muscle without weightlifting’. The cunning plan of these attention

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-seekers involves injecting CRISPR components into the testicles of a male volunteer and then finding a woman to carry the baby. Good luck with that. Lacking the necessary intellectual

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.35 Mitalipov’s team responded to these criticisms, but subsequent studies have found deeply worrying unintended on-target editing outcomes in a wide range of CRISPR applications in various mammalian tissues, including human embryos. Bits of DNA in and around the target gene have been chewed away, sometimes involving deletions

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clear regulatory framework, they concluded, ‘this putative silver bullet technology could become a global conservation threat’. ✴ While these debates were taking place, the first CRISPR-based gene drive was being created, almost by accident. In 2014, Valentino Gantz of the University of California San Diego was finishing his PhD on

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observed by other researchers, studying two different gene drives in Drosophila. Their conclusion was gloomy for some but reassuring for others: The frequency of a CRISPR gene drive in two cages of mosquitoes over twenty-five generations. The upper light grey line shows the expected result. From Hammond et al. (

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2017), PLoS Genetics 13:e1007039. Our results demonstrate that the evolution of resistance will likely impose a severe limitation to the effectiveness of current CRISPR gene drive approaches, especially when applied to diverse natural populations.30 All this had been predicted by mathematical models of gene drives, with researchers pointing

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human body. In 2017, Chinese researchers from George Church’s eGenesis start-up, along with scientists in China and elsewhere, inactivated the retroviruses using CRISPR and were able to clone the resultant cells, producing cute retrovirus-free piglets that appeared on the front cover of Science.27 Three years later

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genetic engineering’s exciting promises is that of the creation of better, stronger and faster-growing plants and cunningly engineered microbes.31 Using TALENs and CRISPR, researchers have created wheat that is resistant to powdery mildew (that would be great for my honeysuckle) and maize that shows improved drought resistance

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with increasing precision, over the last half-century. However, as seen in the recent discoveries about the substantial inadvertent genetic changes induced by ‘editing’ with CRISPR, such metaphors are deceptive. The reality of genetic engineering is far more complex and problematic than pressing a few keys on a computer keyboard. We

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GM demonstration in Oxfordshire, 1998. 15. The announcement of the 2020 Nobel Prize in Chemistry to Emmanuelle Charpentier and Jennifer Doudna for their invention of CRISPR gene editing. 16. Chinese geneticist He Jiankui of the Southern University of Science and Technology in Shenzhen, China, speaking during the Second International Summit on

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cells. One naturally occurring CCR5 allele is associated with resistance to HIV. This was the gene targeted by He Jiankui in his catastrophic use of CRISPR on three human embryos. cDNA (complementary DNA). A DNA sequence that is synthesised by scientists from a mature mRNA sequence using reverse transcriptase. In

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genetically modified organism). A transgenic plant or (more rarely) animal that has been produced by genetic engineering of one kind or another. Guide RNA. In CRISPR, an RNA molecule that specifies the DNA target and directs a nuclease to that location. H5N1. Highly pathogenic avian flu. Occurs frequently in birds but

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TALEN (transcriptor-like effector nuclease). An efficient system of gene editing developed at the beginning of the twenty-first century that was rapidly overtaken by CRISPR. Transfection. Alteration of the genome of a cell by the introduction of recombinant DNA. Transgenic. One of many terms coined to describe an organism

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.sdbonline.org/uploads/files/SDBgenomeeditposstmt.pdf 22 Membres Comité d’Éthique de l’INSERM (2016), Saisine concernant les questions liées au développement de la technologie CRISPR (clustered regularly interspaced short palindromic repeat)-Cas9. https://www.hal.inserm.fr/inserm-02110670/document 23 Quotes from Bosley et al. (2015), p. 481.

The Mutant Project: Inside the Global Race to Genetically Modify Humans

by Eben Kirksey  · 10 Nov 2020  · 599pp  · 98,564 words

Comics series as mutant superheroes fighting for equality and justice. 1978 The world’s first test-tube baby, Louise Brown, is born in England. 1987 CRISPR, or clustered regularly interspaced short palindromic repeats, is discovered by Yoshizumi Ishino in bacteria. The function is unknown. 2000 President Bill Clinton unveils preliminary

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Frankenstein is an apt cautionary tale about the possibility of “devastating discrimination against a bioengineered child.”5 During my international adventures in the world of CRISPR research, I kept science fiction classics close at hand. The rich archive of speculative fiction has helped me understand the perils and potential of

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The New Hope Fertility Center in Manhattan is already advertising a new technique: couples could soon have the opportunity to create designer babies with CRISPR.8 As scientists speculate about postracial futures and nightmare military scenarios, as market forces bring new genetic technologies into the clinic at a dizzying speed

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the human species have already produced atrocities—like the Nazi death camps that systematically eliminated homosexuals and Jews from the population. In the wrong hands, CRISPR could have devastating consequences for humanity. * * * As the controversy swirled around us, everyone wondered if Dr. Jiankui He would show up to be publicly

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engineering technologies. As the lead organizer and chair of the International Summit on Human Genome Editing, Baltimore hoped to establish international guidelines for responsibly using CRISPR. As the world watched that day, Baltimore admitted that scientists could no longer govern themselves. The Nobel laureate declared: “There has been a failure

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and untested procedures. Since many countries lacked clear laws about fertility treatments, Helen O’Neill was concerned that the free market would continue pushing CRISPR into the clinic in countries with lax regulations. As journalists started to speculate about which country might host the next controversial experiment in the global

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infrastructures in “aerospace, cyberspace, and transportation.” The president announced unprecedented support for “modern engineering technologies and disruptive technologies.” Boosters of biotechnology had been hailing CRISPR as one of the most powerful disruptive technologies. As Xi called for “pioneering basic research and groundbreaking and original innovations,” he seemed to be giving

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study seemingly unrelated systems: the structure of animal bodies, the dynamics of global financial markets, emergent strains of the influenza virus, and—fatefully—the CRISPR molecule in bacteria. He defended his dissertation in December 2010, more than a year before Jennifer Doudna and Emmanuelle Charpentier demonstrated how to manipulate DNA

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earlier gene-editing summit on December 1, 2015. Against the backdrop of purple and blue mood lights, with “Sultans of Swing” playing, world-renowned CRISPR scientists mixed and mingled with corporate lobbyists, members of Congress, and other Washington insiders. Jennifer Doudna was there, along with George Church—the Harvard biologist

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“expedited approval pathways” to quickly usher gene editing into the clinic.3 Four start-up companies represented by Michael Werner—Intellia Therapeutics, Editas Medicine, CRISPR Therapeutics, and Caribou Biosciences—had just raised over $158 million in venture capital for gene-editing research.4 Weeks before the summit, Vertex Pharmaceuticals announced

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minorities, and disabled people continued in the United States through the late twentieth century. Oregon kept eugenic sterilization laws on the books until 1983. If CRISPR enters the fertility clinic, Kevles asked, should parents be allowed to make new choices with long-term eugenic consequences? One speaker—Charis Thompson, a

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home, he already has a lot of the necessary laboratory equipment. Since biotechnology lobbyists have consistently pushed against government regulation, anyone can order a custom CRISPR molecule for just $99 on the internet. “I vacillate between how could this be morally or ethically acceptable,” he said, “or even deviantly acceptable

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not currently curable with known and approved therapies.” Having already developed an effective gene therapy for leukemia, June had serious credibility. His proposed use of CRISPR built on new experimental data from his extended team of collaborators. After June finished, a committee member said, “Thank you for the presentation. This

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explained that the RAC set an important precedent with this decision. Going forward, other researchers would not necessarily need to bring their proposals for CRISPR experiments before this committee for approval. Since universities have their own local ethics and safety committees, scientists and policymakers were saying that review at

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Drug Administration. But the biohacking community began to revolt, questioning his exaggerated claims. Josiah Zayner, who was already making waves by distributing do-it-yourself CRISPR kits, made a dramatic public takedown on Facebook, denouncing Aaron for “pseudo-science and medical-huckstery” and joking, “The idea that any scientist, biohacker

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feeding feelings of self-loathing and internalized racism. Molecular biology tools could be quickly commercialized by Asia’s cosmetics industry, exacerbating current trends. With the CRISPR Sperm Bank, Tamara wanted to spark a critical dialogue about the future of race and humanity. Tamara first encountered biohackers in 2014. An obscure

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After carefully studying Donna Haraway’s writing about genetic engineering, I initially had trouble understanding why she was so vehemently opposed to Dr. He’s CRISPR experiment. After all, she had written speculative fiction about parents who genetically engineer their children to embody characteristics of butterflies. In a fictional story,

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’s Science (Stanford, CA: Stanford University Press, 2013). 5: LOOK AT THOSE MUSCLES, LOOK AT THAT BUTT   1   Brandon Lisy, “How Genetic Engineering Tool Crispr Could Change Humanity,” Bloomberg, June 1, 2016.   2   Luoping Zhang et al., “Exposure to Glyphosate-Based Herbicides and Risk for Non-Hodgkin Lymphoma,” Mutation Research

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): 142–44.   2   “Louise Joy Brown,” January 29, 2019, https://web.archive.org/web/20190129073119/https://www.louisejoybrown.com. 22: CHINESE SCIENTISTS ARE CREATING CRISPR BABIES   1   “Code of the Wild Trailer—Genetic Enhancement Is Here,” YouTube, posted by Rhumbline Media, March 15, 2019, https://youtu.be/Wyv3Ibxw-a0.   2

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   Antonio Regalado, “Exclusive: Chinese Scientists Are Creating CRISPR Babies,” MIT Technology Review, November 25, 2018. 23: BUBBLES VANISHING INTO AIR   1   Manya Koetse, “The Controversial Case of the Chinese Gene-Edited Baby Twins

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also genetic testing antibodies antibody therapy for cocaine See also immune system; N6 antibody apheresis. See also immunotherapy Apple (company) Arendt, Hannah (philosopher) art. See CRISPR Sperm Bank; ethics; GFP bunny; Kac, Eduardo; Pertamina, Tamara; Xie, Minjie; Zaretsky, Adam artificial intelligence Ascendance Biomedical Baltimore, David (geneticist) “banality of evil” (Arendt)

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, Louise (first IVF baby) Brown, Timothy Ray (Berlin Patient) Butler, Octavia (science fiction author) cancer Biden, Joe, and Cancer Survivor Hall of Fame first CRISPR clinical trial and inequality and race and See also immunotherapy; Kymriah; leukemia; prostate cancer; Wei, Zexi; Whitehead, Emily; Wilkins, Nicholas Caribou Biosciences CARs (chimeric antigen

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Director of National Intelligence, 2010–2017) Clinton, Bill (president of the United States, 1993–2001) Cohen, Jon (journalist) Cold Spring Harbor Laboratory conflicts of interest CRISPR scientists and death of Jesse Gelsinger and He, Jiankui, and Penn Medicine and coronavirus pandemic cosmetic surgery COVID-19. See coronavirus pandemic Crick, Francis (geneticist

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of price of profit-driven experiments unpredictability of See also Charpentier, Emmanuelle; Church, George; Doudna, Jennifer; He, Jiankui; Huang, Junjiu; ICSI; in vitro fertilization CRISPR Sperm Bank (artwork) CRISPR Therapeutics cryptocurrency “Cyborg Manifesto” (Haraway) cystic fibrosis Daisy, Mike (storyteller) Daley, George (molecular biologist) Darnovsky, Marcy (policy advocate) Darwin, Charles (biologist) Davis,

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Machiavelli (biohacker) Deem, Michael (physicist and bioengineer) co-author of Nature manuscript CRISPR experiment involvement mentor to Jiankui He not charged with crime Defense Advanced Research Projects Agency (DARPA) Deng, Xiaoping (paramount leader, People’s Republic of China

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X-Men and See also ableism; crip; Down Syndrome disability rights Disability Visibility Project Discourse of Race in Modern China, The (Dikötter) diversity biodiversity CRISPR and disability and genetic testing and human neurodiversity science and sexual DNA building block of life databases GenBank history of discovery as a language mutations

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aid parenting vulnerability See also activism; bisexuality; intersex; queer; sexual orientation; transgender community Gelsinger, Jesse (experimental volunteer) gene editing (editing as a metaphor). See also CRISPR; zinc fingers genes basics explained BDKRB2 (vasodilation) CCR5 (HIV resistance) GFP (green fluorescing protein) GFP bunny (artwork) HERC2 (eye color) LRP5 (bone density) myostatin

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s plans for large reproductive clinic medical tourism featured in Boing Boing Han Chinese (ethnic majority) Haraway, Donna (feminist theorist) ACT UP movement and on CRISPR hype Cyborg Manifesto ethics on eugenics on genetically modified children on human-animal genetic hybrids HarMoniCare Hospital Harrington, Mark (HIV activist) He, Jiankui (biophysicist

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and entrepreneur) birth of children of Communist Party and conflicts of interest criminal charges and sentencing criminal investigation CRISPR experiments of education of education at Rice University education at Stanford University education at University of Science and Technology of China education at Xinhua School

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also genes HIV/AIDS AIDS Villages (China) Ascendance Biomedical hacking experiment AZT Baihualin (advocacy organization) Chinese Communist Party and Grindr (dating app) and He’s CRISPR experiment in Indonesia Sangamo gene-editing experiment stigma and discrimination Xi, Jinping, and See also activism; ACT UP; CCR5 gene; immunological nonresponders; inequality; Johnson,

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Technology Policy, the White House, 2009–2017) Holocaust (Nazi) Hsu, Steve (physicist and entrepreneur) Huang, Junjiu (molecular biologist, first to edit human embryo with CRISPR) human-animal genetic hybrids Human Fertilisation and Embryology Authority (UK) Human Genome Project Hunan Province, China Hunt Botting, Eileen (political scientist) Hurlbut, Benjamin (historian) Hurlbut

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, William (physician and ethicist) Hypatia controversy ICSI (inter-cytoplasmic sperm injection) CRISPR and Illumina (genomic company) Immortal Life of Henrietta Lacks, The (Skloot) immune system. See also antibodies; immunotherapy; white blood cells immunological nonresponders. See also HIV

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Summit on Human Genome Editing First Summit (Washington, 2015) Second Summit (Hong Kong, 2018) intersex in vitro fertilization (IVF) birth rates for costs of CRISPR and embryo glue male fertility and sperm injection sperm washing technological limits of womb scratching Ishee, David (biohacker) IVF. See in vitro fertilization Jain, Lochlann

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See mosaic patterns mosaic patterns gene therapy and mutations and Mukerji, Subhas mutagenesis. See mutant mutant art beauty of mutancy cancer mutations CCR5 (HIV receptor) CRISPR targeted mutagenesis disease and diversity fear heritable mutations mutation as resistance normal background mutation rate in popular culture rights screening embryos for mutations special abilities

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gene (muscles). See also genes National Academy of Sciences (China) National Academy of Sciences (US) Proceedings of the National Academy of Sciences report on CRISPR technology (2017) See also International Summit on Human Genome Editing national security. See also Defense Advanced Research Projects Agency (DARPA); MITRE Corporation Nazis and Nazism

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HIV). See also HIV/AIDS Obama, Barack (president of the United States, 2009–2017) O’Donnell, Mary Ann (cultural anthropologist) off-target mutations. See also CRISPR one-child policy (China) O’Neill, Helen (reproductive biologist) Parker, Sean (entrepreneur). See also Sean Parker Institute for Cancer Immunotherapy Patrinos, Aristides (synthetic biologist)

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/AIDS prostate cancer possibility of gene editing causing Putian Group (hospital group) Qin, Jinzhou (embryologist in Dr. He’s laboratory) Bangkok experiment early CRISPR research explaining CRISPR gene editing in embryos prison sentence recruiting volunteers Quake, Stephen (biophysicist and entrepreneur) mentoring of Jiankui He not charged with crime queer celebration community

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fingers Sanger Sequencing. See also DNA; sequencing genes science fiction Altered Carbon (Netflix series) Blade Runner (film) Brave New World (Huxley) “The Camille Stories” (Haraway) CRISPR and Dawn (Butler) dystopian Fantastic Voyage (film) feminist Frankenstein (Shelley) Gattaca (film) genetically modified animals and “Jigsaw Children” (Chan) mutant transformations and Neuromancer (Gibson)

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Skloot, Rebecca (author) SLC24A5 gene (skin color) See also genes; skin color Soccer Genomics. See also genetic testing Southern University of Science and Technology (SUSTech) CRISPR experiment volunteers visit laboratory of Dr. He recruits Dr. He “sports” gene Steptoe, Patrick (obstetrician and gynecologist) sterilization (reproductive) Steven’s Fertility Center (Bangkok)

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test-tube baby. See also Brown, Louise; in vitro fertilization tetra-phocomelia (“four seal’s limbs”). See also thalidomide babies Thailand Chinese medical tourism in CRISPR embryo experiments in Dr. He travels to gay Chinese reproductive tourism in in vitro fertilization in thalidomide babies Thermo Fisher (genomic company) Thompson, Charis (

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, John (fertility doctor), business ventures with Dr. He Zhu, Qingshi (university president). See also Southern University of Science and Technology zinc fingers compared to CRISPR “first-in-human” gene-editing trial 3–D model of See also double-stranded break; editing metaphor Zolgensma (gene therapy). See also drug pricing; gene

She Has Her Mother's Laugh

by Carl Zimmer  · 29 May 2018

DNA inside. Many microbes can chop off the tip of this incoming DNA and insert it into a stretch of its own DNA, called a CRISPR region. (CRISPR is short for clustered regularly interspaced short palindromic repeats.) If microbes manage to survive this initial attack from a virus, they will be equipped

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at the Shanghai Institutes for Biological Sciences in China reported the results of an experiment on mice that suffered from hereditary cataracts. The scientists injected CRISPR molecules into mouse zygotes and they repaired the mutant gene. The altered mice grew up to be fertile adults, and their descendants gazed through

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protein-coding genes sitting on an embryo’s chromosomes. And that change could be inherited by their descendants. The last thing Doudna wanted was for CRISPR to replay the botched history of mitochondrial replacement therapy. That treatment had crept into practice without any public discussion of its ethics, and when

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application in the human germline.” Doudna was choosing her words carefully. From the Napa meeting onward, she wanted to avoid turning public opinion against CRISPR in general. Her fellow scientists would have to restrain their curiosity and not carry out experiments that might seem grotesque or reckless. On the other

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door,” Church told the audience. * * * — In one sense, Doudna’s campaign was a success. She had succeeded in getting a conversation started. By 2016, CRISPR had cracked open its cocoon and was a full-blown media butterfly, the subject of regular coverage on television and in the newspapers. Doudna hopped

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manipulated viable embryos rather than doomed ones. They did everything they could to keep the embryos viable. And while Huang’s team used relatively crude CRISPR tools, Mitalipov took advantage of newer, more precise ones. For their experiment, Mitalipov chose a genetic disease of the heart known as hypertrophic cardiomyopathy.

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That Could End Genetic Disease,” it blared. That evening, I turned on the television at our cottage, only to encounter Mitalipov talking about his experiment. CRISPR was becoming inescapable. * * * — For all the attention the world gave Mitalipov’s research, he didn’t promise much from it. Parents who carry variants

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for hypertrophic cardiomyopathy can already use preimplantation genetic diagnosis to identify embryos that won’t develop the disease. CRISPR might help them deal with simple Mendelian inheritance, which leaves them with only 50 percent of their embryos to implant, lowering the odds of

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single altered animal got into the wild—either intentionally released or accidentally allowed to escape—it could mate with other members of its species. Its CRISPR genes could drive themselves further into a population with every new generation. Under the right conditions, that might be a good thing. Instead of

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just another piece of DNA for us to inject,” he said. * * * — The mutagenic chain reaction hit the news amidst jolting stories about experiments with CRISPR on human embryos. Human genetic engineering had been the stuff of speculation for more than fifty years, since Rollin Hotchkiss had worried over it. But

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Kevin Esvelt, had been musing about the idea. In 2014, they and some of their colleagues published a couple of speculative pieces. But they called CRISPR-based gene drive only a “theoretical technology.” Once Bier and Gantz revealed the mutagenic chain reaction, the technology was no longer theoretical. Esvelt and his

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colleagues reported that they could use CRISPR in yeast to override Mendel’s Law as well. The technology might conceivably work in just about any sexually reproducing species scientists might want to

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alter. As Jennifer Doudna and her colleagues grappled with CRISPR’s use on people, Bier, Gantz, Esvelt, and other scientists began working through the implications of gene drives. At conferences and in scientific reviews,

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Scientists could give genes to an undesired animal that made it less fertile. The animals inheritng these genes would have fewer offspring, but thanks to CRISPR, they would end up in a growing fraction of the population. Eventually, the population would cross a tipping point and collapse. Conservation biologists had

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human heredity,” David Baltimore declared at the international gene-editing meeting in 2015. He was speaking shorthand, one that an audience at a meeting about CRISPR intuitively understood. To them, human heredity was the transmission of genes from human parents to human children. And to them, the looming ability to

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descent with a common ancestral cell in the body. Chromosome: A threadlike structure of DNA and proteins. Humans have twenty-three pairs of chromosomes. CRISPR (clustered regularly interspaced short palindromic repeats): A naturally occurring mechanism that gives bacteria immunity to viruses, allowing them to identify and destroy specific sequences of

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a trillion different species: Locey and Lennon 2016. horizontal inheritance: Daubin and Szöllősi 2016. Enterococcus faecium: Lester et al. 2006. a system of molecules called CRISPR-Cas: Zimmer 2015a. a genuine case of Lamarckian heredity: Koonin and Wolf 2009. These microbial monsters were eukaryotes: Dacks et al. 2016. meiosis: See

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2017; Doudna and Charpentier 2014. “We had built the means”: Doudna and Sternberg 2017, p. 84. Rudolf Jaenisch: Wang et al. 2013. the parade of CRISPR animals became a stampede: Ledford 2016. “To me the interest was how . . .”: Cold Spring Harbor Lab 2013. Lippman and his colleagues planted the seeds

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Twentieth-Century America.” In Blood Will Out: Essays on Liquid Transfers and Flows. Edited by Janet Carsten. London: John Wiley & Sons. Ledford, Heidi. 2016. “CRISPR: Gene Editing Is Just the Beginning.” Nature 531:156. Lein, Ed, and Mike Hawrylycz. 2014. “The Genetic Geography of the Brain.” Scientific American 310:70

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of Iodine Deficiency.” Nature Reviews Endocrinology 8:434–40. Liang, Puping, Yanwen Xu, Xiya Zhang, Chenhui Ding, Rui Huang, Zhen Zhang, and others. 2015. “CRISPR/Cas9-Mediated Gene Editing in Human Tripronuclear Zygotes.” Protein & Cell 6:363–72. Librado, Pablo, Antoine Fages, Charleen Gaunitz, Michela Leonardi, Stefanie Wagner, Naveed Khan

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Village Voice, February 23, pp. 31–38. Noble, Charleston, Jason Olejarz, Kevin M. Esvelt, George M. Church, and Martin A. Nowak. 2017. “Evolutionary Dynamics of CRISPR Gene Drives.” Science Advances 3:1601964. Noguera-Solano, Ricardo, and Rosaura Ruiz-Gutiérrez. 2009. “Darwin and Inheritance: The Influence of Prosper Lucas.” Journal of the

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. Schwank, Gerald, Bon-Kyoung Koo, Valentina Sasselli, Johanna F. Dekkers, Inha Heo, Turan Demircan, Nobuo Sasaki, and others. 2013. “Functional Repair of CFTR by CRISPR/Cas9 in Intestinal Stem Cell Organoids of Cystic Fibrosis Patients.” Cell Stem Cell 13:653–58. Schwann, Theodor. 1847. Microscopical Researches into the Accordance in

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S. Shivalila, Meelad M. Dawlaty, Albert W. Cheng, Feng Zhang, and Rudolf Jaenisch. 2013. “One-Step Generation of Mice Carrying Mutations in Multiple Genes by CRISPR/Cas-Mediated Genome Engineering.” Cell 153:910–18. Wang, Michael. 2012. “Heavy Breeding.” Cabinet magazine, Issue 45. Wang, Zhang, and Martin Wu. 2015. “An

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536 Avdonin, Alexander, 175–76 Avery, Oswald, 140–41, 508 Ayash, Chen Aida, 541 bacteria and cell division, 323–24 and cell theory, 326 and CRISPR system, 143–44, 488–89 and discovery of genes, 124 environmental influences of, 564 and evolution of DNA-based life, 138–42 and genetic engineering

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Carmi, Shai, 224 Carnegie, Andrew, 62 Carnegie Institution, 62, 79 Carter, Jimmy, 511, 512 Cary, S. Craig, 409 Cas enzymes, 143, 489. See also CRISPR/Cas system cattle, 48, 370–76, 378 cell lineages and chimerism, 379, 382, 384, 392–93, 401 and embryonic development, 331–32 and engineering of

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216, 218 Christensenella, 415–17 chromosomes and bacterial reproduction, 323 and causes of PKU, 129, 133 and chimerism, 380–81, 386–91, 393, 398 and CRISPR mechanism, 143, 494, 523, 525, 552–54, 558, 573 and discovery of genes, 123–24 and Drosophila research, 98 and embryonic development, 328 and epigenetic

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Cristina, 442 Cowdry, Edmund, 417–18 Crabbe, John, 301 Craven, Isabel, 72 Creger, William, 385 cretinism, 70, 306. See also feeblemindedness Crick, Francis, 124–25 CRISPR/Cas system and Drosophila research, 550–54 early research on, 488–91 and ethical issues of scientific advances, 542 and genetic vs. nongenetic heredity, 474

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Paul, 454 “The Elimination of Feeble-Mindedness” (Davenport), 85 Ellis, Erle, 570 Ellison, Jane, 521 embryos and embryonic development and chimerism, 382, 385, 391 and CRISPR research, 496–97, 560, 565 early theories on, 324–33 and engineering of embryonic cells, 543–49 and epigenetics, 436–37, 440–42 and ethical

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6 and genetic vs. nongenetic heredity, 471 and heredity within individuals, 323–24 and human germ line engineering, 523–28, 530–34 and impact of CRISPR technology, 538 and inheritance of behavioral traits, 430 and lineage of cells, 333–38 and lyonization, 337–42 and microbiomes, 413 mitochondria, 421 and

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547 endosymbiosis, 410–17, 419 Enlightenment, 256–57, 427 Enterococcus faecium, 141 epigenetics and epigenesis and animal biology, 440–42 and cell lineages, 344 and CRISPR research, 566 and embryonic development, 325, 332 and environmental influences, 430–34, 466 epigenome described, 430–34 and fetal alcohol syndrome, 479–80 and genetic

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528 eukaryotes, 144, 152–54, 418–19 evening primroses, 61–62 evolution and acquired traits, 427 and brain development, 469 and chimerism, 399–401 and CRISPR technology, 561 and cultural inheritance, 445, 461, 463 of DNA-based life, 138–39 and endosymbiosis, 410 and environmental impact of humans, 570 and environmental

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129, 180, 183, 317 Génin, Emmanuelle, 280 genocide, 64, 84, 100, 121–22 genome sequencing and base pairs, 125 and chimerism, 381, 393, 396 and CRISPR system, 488–90 and Denisovan DNA, 248 and exome sequencing, 357 and genetic testing and counseling, 2–3, 129, 133, 183–86 and height research

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enzymes, 487 and technological advances, 504 and tracing lineages, 177, 191 genome-wide association studies, 277–78, 280–83 germ cells and germ lines and CRISPR technology, 524 and epigenetics, 439, 442 and genetic vs. nongenetic heredity, 472, 478–79 and Germinal Choice program, 501–4, 507, 534–35, 540

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and chimerism, 380 and ethical issues of scientific advances, 541 and genetic screening, 504–7 and human germ line engineering, 533–34 and impact of CRISPR technology, 538 and mitochondrial replacement therapy, 517–22 and ooplasm transfers, 513–17 and preimplantation genetic diagnosis, 535 and in vitro gametogenesis, 546–49 iodine

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27, 84 Merikangas, Kathleen, 276–77 Merrick, Joseph (the Elephant Man), 351–52, 356 Mesoudi, Alex, 464 Metamorphoses (Ovid), 484 methyl groups and methylation and CRISPR system, 489 and epigenetics, 430–31, 433–34, 436–41, 566 and genetic vs. nongenetic heredity, 479 and lyonization, 338 and the Peloria plant, 425

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393 microsatellites, 381, 393 Mitalipov, Shoukhrat, 517, 530–32, 537–38 Mitchell, Kevin, 437 mitochondria and mitochondrial DNA and chimerism, 399–400 and development of CRISPR technology, 523 and environmental influences, 466 and genetic vs. nongenetic heredity, 472 and human/Neanderthal interbreeding, 244 and mitochondrial replacement therapy, 517–22, 542, 548

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Elon, 497 mussels, 398, 421 mutations and alleles, 125–26 beneficial, 149–50 and causes of PKU, 131, 132 and chimerism, 392, 394–99 and CRISPR research, 490, 496, 531–32, 538–40, 542 and diagnosis of hereditary diseases, 133–34 and Drosophila research, 97–99, 499 and embryonic development, 331

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and evolution of DNA-based life, 139 and genetic vs. nongenetic heredity, 475–78 and height, 269 and human-altered environments, 468 and impact of CRISPR technology, 539–40 and mutation load, 501 and skin color, 230 and Weismann’s germ line theory, 57 nature vs. nurture, 245, 263, 298,

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James, 361–66 primates, 413–14, 458–60. See also hominins primordial cells, 138, 440 Pritchard, Jonathan, 214–16, 218–19, 283–84 proteins and CRISPR system, 495–96 and epigenetics, 431 and evolution of DNA-based life, 138–39 and freemartins, 373 and genetic vs. nongenetic heredity, 475 and height

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458 restriction enzymes, 489 retrotransposons, 441 RFMix, 222, 223 Rh factors, 208 Risch, Neil, 276–77 RNA (ribonucleic acid) and bacterial restriction enzymes, 488 and CRISPR system, 489–91 and DNA replication, 125 and epigenetics, 439–42 and evolution of DNA-based life, 138–39 and gene drives, 155 and genetic

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428 Skinner, Robert and Judith, 254 SLC24A5 gene, 231, 233 slipper limpets, 329–30 Smith, David, 479 Society of Friends, 287–88 somatic cells and CRISPR technology, 524 and engineering of embryonic cells, 544, 546 and epigenetics, 439, 442 and genetic engineering, 511 and human germ line engineering, 526–27 and

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392–400, 472. See also cancers Turkheimer, Eric, 310–11 Turnbull, Doug, 517 23andMe, 180, 182, 240–42 twins and chimerism, 380–82, 384 and CRISPR research, 497 and effects of meiosis on heredity, 151–52 and ethical issues of scientific advances, 541 and freemartins, 370–72, 373–76, 378–79

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Wolverton’s admission to, 68–73 Virchow, Rudolf, 326 viruses and bacterial restriction enzymes, 487 and chimerism, 392–93, 395, 397–98, 400–401 and CRISPR mechanism, 143–44, 488–89, 524 and gene therapy, 511–12, 532 and horizontal inheritance, 142 and Mendel’s Law, 473–74 and retrotransposons,

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150–51, 251–52, 344 Zimmer, William, 4, 157 Zimmer, Wolf, 221 Zioberg, Magnus, 422–23 zygotes and ancestral overgrowth, 327 and chimerism, 393 and CRISPR research, 496 and embryonic pedigrees, 329 and freemartins, 374 and human germ line engineering, 525 and microbiomes, 407 and mosaicism, 355, 357, 360, 366 and

Warnings

by Richard A. Clarke  · 10 Apr 2017  · 428pp  · 121,717 words

to induce a pandemic. They are unlikely to be the last. In chapter 16 we will assess the risks from the gene-editing tool called CRISPR. CRISPR’s greatest threat may be its use as a tool to create lethal diseases. Even hardened experts like Dr. Webster, who fight every day against

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is too late. But now, my god . . . when you have competing weapons programs out there and kids are creating previously nonexistent microorganisms . . .” Accepting that the CRISPR technology will be around for the indefinite future, Garrett still maintains that a better public health surveillance-and-response system is the only way to

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of the twenty-first century North Korean scientists surreptitiously perfected a low-cost and efficient technique to modify the genes of human embryos. Known as CRISPR/Cas9, it was previously used ubiquitously and admirably around the world, curing humankind’s genetic diseases, helping livestock grow faster and larger, and making

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a highly acidic abandoned mine. The genetic material of many of these bacteria, Dr. Banfield said, contains numerous “clustered, regularly interspaced, short, palindromic repeats,” or CRISPR for short. In essence, some of the DNA repeats itself. Over the years, scientists realized that there are “spacers” between these repeated sections, and that

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University in Sweden, was studying the genome of flesh-eating bacteria. She and her colleagues had been investigating the process by which bacterial CRISPR sequences, coupled to a CRISPR-associated (Cas) protein, protect the cell from viral invasion. Charpentier hoped to recruit the well-known structural microbiologist to their effort and

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other is an activating strand that doesn’t itself bind to the target DNA but is necessary for the complex to function properly. Altogether, this CRISPR/Cas9 structure efficiently and accurately slices up the matching DNA from an invading virus.4 The eureka moment—when, as Professor Doudna describes it, “

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Charpentier, and their teams had created a tool that could slice open the DNA of any organism at any point they specified, and the artificial CRISPR/Cas9 complex worked just as efficiently and effectively as it did in nature. At that moment, they realized that their exploration had transcended basic research

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material were combined with other favorable traits and passed on to future generations, resulting in more and more desirable organisms.6 The revolutionary aspect of CRISPR/Cas9 is that scientists can now potentially isolate and edit genes in a single generation that would have traditionally taken scores of generations to change

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animals with longer hair and more muscle, ostensibly better at producing both meat and wool. In fact, dozens of Chinese labs have plunged headlong into CRISPR/Cas9 experimentation in fields ranging from animals to agriculture to biomedicine to human transformation.7 Personalized medicine and the elimination of genetic disorders is another

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potential bright spot in the future of CRISPR/Cas9. Scientists can now snip out defective genes that cause disease, replacing them with healthy ones. Such a procedure would be most easily carried

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out for conditions caused by a single genetic mutation, such as sickle-cell anemia, Huntington’s disease, or cystic fibrosis. A CRISPR-based therapy would substitute a properly functioning gene for the defective section of DNA in the patient’s cells. In an extraordinary 2013 experiment, scientists

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code prevents the liver from producing an important enzyme, which causes toxins to build up in the body and often requires a liver transplant. Using CRISPR/Cas9, the researchers were able to splice functioning DNA sequences into the mouse liver cells, restoring proper liver function.8 Similarly, researchers at the University

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of Texas Southwestern Medical Center successfully used CRISPR/Cas9 in 2015 to treat Duchenne muscular dystrophy, a more common incurable disease that affects about 1 in every 3,500 boys and causes the

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fixing human disorders caused by multiple genes—like amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease) and many types of cancer—presents additional complications, CRISPR/Cas9 is already being used by medical researchers to engineer away analogous diseases in animals. These animal models are facilitating more accurate and effective research

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population collapse? And considering the public outcry about classically genetically modified organisms, how freaked out will (and should) the public be when scientists start using CRISPR to tweak the DNA of our grocery-store produce, making salmon a brighter orange and giving tomatoes and cucumbers a longer shelf life?11 Another

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serious concern arises from what are known as off-target events. After its discovery, researchers found that the CRISPR/Cas9 complex sometimes bonds to and cuts the target DNA at unintended locations. Particularly when dealing with human cells, they found that sometimes as many

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cells. But those somatic genetic edits would remain only with that single individual, passing away with its death, and would not affect future generations. Using CRISPR to treat a woman suffering from tyrosinemia, for example, would genetically modify her liver cells, but her children, should she later become pregnant, would lack

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the improved gene. However, CRISPR can also modify the DNA of a fertilized egg or embryo. As its cells divide and mature into a fully-formed human being, every cell

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procreating? Would such a restriction even be feasible, let alone ethical? These questions aren’t simply thought experiments. In 2014, researchers in Nanjing, China, used CRISPR/Cas9 to carry out gene editing in the embryos of cynomolgus monkeys, the first time the technique had been used successfully in primates. Cynomolgus monkeys

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experimentation next.13 While her research focused on some of the smallest molecules present in microscopic bacteria and viruses, Professor Doudna knew the implications of CRISPR were huge. She began growing uneasy with each new revelation pointing toward the inevitable ramifications of the tool she had helped to create. At first

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discovered restriction enzymes, enzymes that cut DNA at a single, specific sequence of nucleotides. Each restriction enzyme is specific to a certain DNA sequence, whereas CRISPR can be modified and customized to cut DNA wherever you like. Around the same time, scientists had also discovered an enzyme called DNA ligase, which

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also gave way to the reality that manipulating DNA, precisely specifying the cutting location, proved surprisingly tricky. It remained that way until Professor Doudna’s CRISPR breakthrough. Still, Asilomar is credited with serving an even more important role. Dr. Berg explained to us in his Stanford office, where he still

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discovered, and the scientific community again needed to figure out a way forward. Like Dr. Berg and recombinant DNA technology, Professor Doudna, the inventor of CRISPR, was now a leader in the effort to understand and prevent the possible unintended consequences that could result from its unfettered deployment and adoption. Given

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the type of experimentation already underway using CRISPR, the questions the scientists at Napa tackled were markedly different from those at Asilomar. “We never discussed ethics,” Dr. Berg told us, “and we

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basic research that might one day be applicable to engineering human genetics. Just as significantly, the Napa group called for better communication and discussion about CRISPR. Doudna, Berg, Baltimore, and the other attendees believed that an open and frank discussion among the public, scientists, legal experts, bioethicists, and other stakeholders

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was that public trust in science ultimately begins with and requires ongoing transparency and open discussion. That lesson is amplified today with the emergence of CRISPR-Cas9 technology and the imminent prospects for genome engineering. Initiating these fascinating and challenging discussions now will optimize the decisions society will make at the

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small, its participants were influential. The Napa attendees hoped that their commentary would buy some time in forging a broader consensus on the use of CRISPR. At the very least, they hoped human germ-line editing remained simply a fiction. Two weeks after the Napa commentary was published, Chinese scientists

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DNA of human embryos at all was itself significant.21 If nothing else, the study did exactly what Professor Doudna hoped to avoid: it thrust CRISPR into the public consciousness in an unsettling and alarming way. The Washington Post carried the headline “The Rumors Were True: Scientists Edited the Genomes

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her briefing to the House Committee on Science and Technology. On her second trip to Congress, Professor Doudna and some of her colleagues involved with CRISPR held an all-day public meeting in Washington, D.C., attended by members of Congress, staffers, students, and the general public. “The astounding thing

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able to edit the human genome in a way that will change evolution, that something profound was happening in science.” Their main message remained that CRISPR should not yet be used to modify the human germ line and that, while research on treating human diseases should certainly continue, the public

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human genome is 1/100,000 that number), about the same rate that genetic errors occur naturally. Still, darker questions surrounding the future applications of CRISPR remain at the margin, and not just in the minds of conspiracy theorists. In a November 2015 interview with the New Yorker, Professor Doudna said

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and the Napa group alluded. Simple in vitro fertilization currently costs upwards of $10,000, but gene editing would likely cost many times more. Could CRISPR become a tool for the wealthy elites to engineer genetically superior babies? In a world already racked by increasing wealth inequality and an increasingly distinct

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In the 1997 movie Gattaca, genetic information and modification became a tool used to correct imperfections while stratifying the masses into de facto castes. Could CRISPR irreversibly and forever create a privileged segment of society with superior intelligence, looks, and health via a self-perpetuating cycle of self-selection? Previous advances

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in genetic technology also raised the specter of eugenics, but never before has the tool been as simple, efficient, and promising as CRISPR/Cas9. If the elites can harness the power of gene editing for the benefit of their offspring, governments too could harness the capability as a

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means to bolster the country’s power, maximizing its human capital, and more specifically, its intellectual capacity. Failing to exploit CRISPR could become a national security liability. Jamie Metzl is a novelist and biotechnology policy expert at the Atlantic Council. Formerly a colleague of ours on

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Professor Doudna and many of her colleagues still fear that the wider public is unprepared to understand, let alone debate, all of the implications of CRISPR/Cas9. These questions aren’t relevant only to Americans, the conversation must transcend national boundaries. In December 2015, ten months after the Napa Conference

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and nearly eight months after the Chinese scientists published their paper on editing human embryos with CRISPR, the International Summit on Human Gene Editing was held in Washington, D.C., sponsored by the U.S. National Academy of Sciences and National

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the United Kingdom. As the Napa Conference was meant to be only a starting point for a further discussion on the future and implications of CRISPR/Cas9, several members of the Napa Conference, including Drs. Doudna, Baltimore, and Berg, sat on the summit’s organizing committee. Over three days, scientists,

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or would it exacerbate global inequality? Are current international bodies and mechanisms capable of establishing a global governance infrastructure for the oversight and use of CRISPR? Or is international oversight simply a pipe dream?26 Like the Napa Conference, the summit produced opposing viewpoints and few clear answers. And like the

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, more robust round of ethical and regulatory debate. It called for ongoing basic research and prudent precautions in moving toward any therapeutic use of CRISPR/Cas9 in human somatic cells, as well as for an ongoing international discussion on the role and use of gene editing technology in the future

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being considered outlandish, researchers and bioethicists have already initiated robust discussions with policy makers on the implications of the technology. The headline-grabbing nature of CRISPR has already begun to generate significant public awareness, which these same scientists recognize must be informed by open and accurate information from academia. Professor Doudna

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, if it will be used to enhance rather than simply fix. An unknown also arises from how effectively a new set of global norms around CRISPR will be adopted by the international community. As we have seen with artificial intelligence, pandemic disease, and other warnings, diffusion of responsibility is a

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Cassandra, and the critics. The responses to these warnings range from the promising, like the concerted effort to create global norms around the use of CRISPR/Cas9, to the piddling, like the nascent struggle against artificial intelligence’s possible threat to humankind. Our intent was not to take sides, but rather

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react. This judgment becomes crucial. How much time will we have? Professor Jennifer Doudna hopes that current efforts to establish norms around the use of CRISPR/Cas9 technology will succeed. Perhaps monitoring the use of the technology will be enough. In the case of a large Earth-bound asteroid, David Morrison

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include deeply buried errors, inefficiencies, and vulnerabilities. Coding errors are no longer a problem just for computer software. Edits to the human genetic code using CRISPR/Cas9, perhaps to remove disease-causing defects, perhaps to enhance physical attributes, may have unintended consequences years or even generations later. We do not yet

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Pollack, “Jennifer Doudna, a Pioneer Who Helped Simplify Genome Editing,” New York Times, May 11, 2015, www.nytimes.com/2015/05/12/science/jennifer-doudna-crispr-cas9-genetic-engineering.html?_r=0 (accessed Oct. 11, 2016). 4. Martin Jinek et al., “A Programmable Dual-RNA–Guided DNA Endonuclease in Adaptive Bacterial

Decoding the World: A Roadmap for the Questioner

by Po Bronson  · 14 Jul 2020  · 320pp  · 95,629 words

Startups THE HUSTLE 4. 33.48 Tons of Dead Fish Collected in Pinellas County as Red Tide Bloom Lingers ABC ACTION NEWS 5. Mail-Order CRISPR Kits Allow Absolutely Anyone to Hack DNA SCIENTIFIC AMERICAN 6. The Mystery of Vanishing Honeybees Is Still Not Definitively Solved SCIENCE NEWS 7. What Colors

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CNBC 22. Billionaire Warren Buffett Calls Bitcoin “Rat Poison Squared” COINDESK 23. These Countries Are All Building Brand-New Cities WORLD ECONOMIC FORUM 24. How CRISPR Will Change the World BLOOMBERG 25. The “Blood Boy” Clinic Is Coming to NYC So Rich People Can Live Forever MASHABLE 26. The Meaning of

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wanted to start a clinical trial in 10 days. Melanie needed 32 days to grow antibodies and sequence them. Franco needed 45 days for his CRISPR test, which would drop the cost of testing to five dollars. First went the handshakes. Second went travel. Everyone canceled their trips. Even in a

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we’ll eat beef meatballs without killing cows. • That rich people won’t age. • Everyone’s going to get $1,000 a month, for nothing. • CRISPR will lead to a new transhumanist species. Taken together, it’s a pretty strange future being painted. And the natural reaction—probably the safest option

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those shows is a warning against passiveness. Don’t be a sheep or this will happen to you. 5 Mail-Order CRISPR Kits Allow Absolutely Anyone to Hack DNA Scientific American CRISPR wasn’t the first way to edit the genome, just like the Apple Macintosh wasn’t the first computer. But

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there was something about CRISPR’s ease of use (at least the way it was portrayed in the media) that made it seem like it would lead to this great

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gene editing—the biological equivalent of every home having a desktop computer connected to the internet. Rather quickly, there were reports of high schoolers doing CRISPR in biology class. Plenty of people found this inherently scary. Pundits raced to the microphones to declare themselves the voice of temperance. Slow down, they

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of the things that really gets under my skin is when policy wonks go on television and say, “We need to have a conversation about CRISPR and where gene editing is going.” Editorials are penned that urge, “It’s going to have to be regulated.” Threat scenarios of rogue geneticists and

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conferences and openly talking about their work has been a fundamental principle of science before and after. Yes, high school science classes use gene-editing CRISPR kits today. They also use chemical agents. They also program computer code. They are about as dangerous as Mentos dropped into a Coke bottle. A

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so that someone can’t get around the screening by ordering from multiple companies. In a similar way, we were all disturbed when the rogue CRISPR-Baby scientist, He Jiankui, presented his work on the two girls he tried to genetically immunize from their father’s HIV infection. To pull it

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didn’t have a way to report him. Now they do. Over the course of this book, we’ll get into a better understanding of CRISPR, and why it’s a lot harder to use on a multicellular organism than commonly portrayed. The most common nightmare scenario offered is not a

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rogue academic. It’s that some high schooler will accidentally create a mutant bacteria and release it into the world. (High school CRISPR kits edit an E. coli bacteria genome.) What people don’t realize is that all bacteria are constantly mutating already. Bacteria have a way to

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swap DNA on their own—and they don’t need CRISPR to do it. Every time we use antibiotics, we fundamentally force bacteria to mutate to try to escape. Of the trillion species of bacteria,

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fewer than a hundred are pathogenic to humans. Introducing CRISPR into this mad scramble is like bringing a Philadelphia Eagles jersey to a football game at Lincoln Financial Field. It does absolutely nothing, because every

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fan already has an Eagles jersey—just like every bacteria already has CRISPR in it. (CRISPR comes from bacteria.) I think it’s time to bring into this discussion the CEO of Twist Bioscience, Emily Leproust. Twist Bioscience is a

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-off dystopian future. In the case of bees, dire predictions about a world without bees. We see this warp-speed impulse all the time. When CRISPR was invented, almost immediately people were talking about the future horror of designer babies. The driverless car led people to impulsively jump ahead to a

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dish we’re going to prepare today is called “A Better Way to Do Kidney Transplants.” Dimitre would prefer to call it Immune Regulation via CRISPR knock-ins of IL10 to T-Regulatory Cells. Which just isn’t as catchy. The challenge of kidney transplants is that the patient’s immune

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. Notice we don’t need the patient. He can stay at the hospital. Dimitre is not going to inject the patient’s body directly with CRISPR. Instead, the physician at the hospital would draw the patient’s blood and send it to Dimitre, who will genetically engineer the desired immune cells

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. Only the cells that are perfectly CRISPRed get injected back into the patient. This avoids all sorts of problems and makes his solution very elegant. For today, we’re using blood Dimitre

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days. Epidemiologists study people’s health over the long term and try to sort out why they’re falling ill. But in an era of CRISPR babies, longevity drugs, and bioprinting replaceable organs, epidemiology isn’t exciting. You just don’t read as much science news anymore where volunteers were studied

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. When you see this on a daily basis, you come to understand that genetic machinery is insanely diverse in every dimension. One startup is using CRISPR, yes. One is using recombination. One is using viruses. One is using zinc fingers. One is using directed evolution. These are the classic ways to

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do it though. Leave all this? Would you have more money to deploy? Way way more. 24 How CRISPR Will Change the World Bloomberg Let’s just get this out of the way. CRISPR will not change the world. Not anytime soon. OK? Whew. Like ripping off a Band-Aid. Let’s

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of this hill clean like a giant, God-like leaf blower. I’m here to experience firsthand the extreme conditions that give rise to novel CRISPR-Cas enzymes. I push the door open against the unflagging wind. I’m hit full force with the Patagonian gale, and I stagger a bit

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other, cut off from the rest of Earth. It’s in extreme-yet-isolated conditions, such as this barren place, that bacteria’s CRISPR systems evolved differently. These CRISPR systems might cut genes differently, or perform the same cut but at a different temperature. Or they might destroy viruses not found anywhere

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bag to take samples back to the lab. Instead I take a photo as a consolation prize. My mind drifts to the monumental discovery of CRISPR and the ensuing patent jam. It strikes me that innovation and evolution are one and the same. Nature has invented the greatest gene editor, but

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patent fight between UC Berkeley and the Broad Institute (a collaboration of MIT and Harvard) keeps on going, appeal after appeal. Which really sucks because CRISPR technology is good. It’s as if researchers were doing 85 mph on the freeway toward innovation city and suddenly hit bumper-to-bumper traffic

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same time. Both teams filed patents. Both teams claim they were first to file. Both institutions are fighting to the death over the rights to CRISPR for a simple reason: cash money. Billions of dollars of licensing royalties are at stake. And the reputations of their hallowed institutions. This East Coast

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makes Tupac versus Biggie look small. Even if the two sides in the patent case settled their dispute, CRISPR wouldn’t be available to everyone to use. You may think everyone can use CRISPR and just pay a royalty, but that’s not how it works. A small group of companies paid

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licensing fees to each patent holder for exclusive rights to use CRISPR in certain domains—therapeutics, diagnostics, agriculture, and the like. This is tantamount to the inventor of the movie projector, Eadweard Muybridge, saying only this handful

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full product development and getting to market as soon as they could without the fight. There are only two uses of CRISPR approved in humans. One is for inherited blindness—CRISPR works in the eye because the eye is not defended by an immune system (which anywhere else in the body would

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attack CRISPR). The second is for spinal muscular atrophy, the leading genetic cause of death for infants. But the treatment damages the liver, as the liver tries

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to clear the virus from the body. We have funded a few companies that use CRISPR technology for different applications. Dahlia is a diagnostics company that uses a modified version of Cas9, also invented by the Doudna lab, to glow when

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it binds to RNA. Dahlia was able to get a license because its founder, Un Kwon, was an executive at Caribou Therapeutics, another Doudna lab CRISPR spinoff. Dahlia is building a research tool to see which genes are active at any given time, and sort the cells based on the level

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have a license from the select group of patent holders. Even though one of their advisors, Luciano Marraffini, was one of the early coinventors of CRISPR. Marraffini has stayed away from the patent fights, wanting nothing to do with them. Without a license, Caspr—our company—has had to look for

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novel CRISPR mechanisms. Caspr just completed an expedition to a remote area near Salta, an alien landscape pocked with tomato-red pools and boiling mud pots, where

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coronavirus infection. It doesn’t diagnose symptoms, like other tests. It detects corona at the DNA-matching level. So Caspr isn’t using CRISPR to edit the genome; it’s using CRISPR to detect the presence of a code—in this case, coronavirus—but they’ve also done Zika and many superbugs

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Caspr team is good. Really good. But the machinery of capitalism and patent protection wants to erase them from the earth. Go away, you innovators! CRISPR belongs to us! I flew to Argentina to keynote their national biotech conference. But Argentina is also the perfect place to get a perspective on

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new drug targets and knowledge of biological systems. César Milstein was selfless in his act of prioritizing society over personal wealth, and millions have benefited. CRISPR is monoclonal antibodies all over again. But this time, there is no César Milstein. Back in Buenos Aires, I meet with Mariano Mayer, the secretary

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are ironclad once issued but take years to grant. The trade-off for speed through the patent system is the mess at the heart of CRISPR today. I sip my coffee, and Mariano sips his maté. We now begin to follow the thread of patent law. Once a patent is

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brightens. “That’s a compromise that could work,” he muses. I think even Caspr would go for it. Mariano adjusts his long, rectangular black eyeglasses. CRISPR works nearly perfectly on cells in a petri dish. But in a human guarded by an immune system, we’re not there. This is one

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of the most important lessons you can possibly take away from this book. At IndieBio, we use CRISPR almost every day. Lab work is not under the license restrictions. We edit cells. We program cells, and then we tweak the program

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successfully deliver a gene, we can never do it again. The immune system uses T cells and antibodies to remember enemies. Even if we get CRISPR past the immune system to the cells in our body, there are off-target effects. The guide RNA is eighteen to twenty base pairs long

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or fatal side effects as it turns off random genes in the patient’s genome. At IndieBio, we are investing heavily in ways to sneak CRISPR past the immune system, and to avoid these off-target effects. But even with these massive problems to solve, before it can be used on

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humans, CRISPR is widely regarded as being worth hundreds of billions of dollars. My next meeting adds a different voice to the conversation. I arrive at a

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piles into a room, and Franco gets his team on the phone from Argentina. “We found a way to get our own method-of-use CRISPR patent,” Franco announces. “Walk us through it,” I ask. “To be patentable, it has to both be different and improve performance,” Franco says. “We’

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,” Franco responds. That means it’s patentable. Franco clarifies that they may still need a license because they’re still building on the foundation of CRISPR. But now that Caspr has its own patent—and a better solution—it has more leverage at the bargaining table. I couldn’t be more

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color and intelligence, worried that the only fairness of life left—the randomness of our genes at birth—can be stolen by a scientist and CRISPR. But I’m not as worried about it, and there’s a reason why. I think that story line—“designer baby” clickbait—is misreading

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t they? Isn’t that what the Chinese guy did?” In 2018, headlines roared around the world that a Chinese scientist named He Jiankui used CRISPR Cas9 to edit two human embryos to become immune to HIV. Two edited little girls were born. Over the next months we learned more about

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replicate a mutation in the CCR5 gene that occurs naturally in about 1 percent of people; it makes them immune to HIV. When Jiankui injected CRISPR into the embryo of an HIV-positive man and a woman, it scanned the genome for the CCR5 gene, which allows HIV to enter the

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cell. When CRISPR finds its target sequence, it stops and cuts the DNA in that spot, disabling the gene and closing the door to HIV. The reality is

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the cut doesn’t happen immediately, and CRISPR activity is short-lived. Only about 80 percent of the cuts and necessary repair will happen on the first day, and then a bit more

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so nothing happens. Twenty years ago, this field of small-RNA interference was on the brink of being the kind of REALLY BIG NEWS that CRISPR is today. It seemed to explain a really big hole in science, which was that we couldn’t reliably match genotype to phenotype. In so

The Business of Platforms: Strategy in the Age of Digital Competition, Innovation, and Power

by Michael A. Cusumano, Annabelle Gawer and David B. Yoffie  · 6 May 2019  · 328pp  · 84,682 words

Carmelo Cennamo. In addition, Ganesh Vaidyanathan helped with the quantum computing discussion; Samantha Zyontz, as well as Gigi Hirsch and David Fritsche, helped with the CRISPR discussion. Several research assistants helped with the platform company database and analysis. We thank Danny Nightingale, Damjan Korac, Georges Xydopoulos, and Ankur Chavda (who provided

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or two, with their own technological, regulatory, and ethical challenges: the race to commercialize quantum computers and ongoing efforts to apply and build ecosystems around CRISPR technology for gene editing. We conclude that the age of unfettered, open platforms is largely over, and that platform businesses need to self-regulate or

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as well as to work with governments, which are likely to play a major role in overseeing at least some quantum computer applications and services. CRISPR: AN INNOVATION PLATFORM FOR GENE EDITING Gene editing—altering DNA to modify the characteristics of plants, animals, and even people—was already a global market

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platforms and ecosystems, similar to what we have seen in quantum computers and other industries.31 One particularly promising technology is CRISPR, or “clustered regularly interspaced short palindromic repeats.”32 CRISPR refers to small pieces of DNA that bacteria use to recognize viruses. What scientists observed years ago is that specialized segments

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the immune system in bacteria fight against an invading virus. In 2012, several scientists discovered they could use CRISPR sequences of DNA as well as “guide RNA” to locate target DNA and then deploy CRISPR-associated enzymes as “molecular scissors” to cut, modify, or replace genetic material. The potential applications include diagnostic

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tools and treatments for genetic diseases as well as genetic reengineering more broadly.33 An August 2016 article in National Geographic magazine described CRISPR’s potential: CRISPR places an entirely new kind of power into human hands. For the first time, scientists can quickly and precisely alter, delete, and rearrange the

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years, the technology has transformed biology. . . . No scientific discovery of the past century holds more promise—or raises more troubling ethical questions. Most provocatively, if CRISPR were used to edit a human embryo’s germ line—cells that contain genetic material that can be inherited by the next generation—either to

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a human embryo’s germ line is not simply a hypothetical possibility. In December 2018, reports surfaced that a “rogue” Chinese scientist already had used CRISPR to disable a gene in twin unborn babies that would make them resistant to HIV. The scientist reportedly couldn’t disable both copies of the

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have already created products, tools, and components that other firms are building upon. Like today’s quantum computers, however, there are limitations. Each use of CRISPR requires specialized domain knowledge, such as the genome of a particular organism and disease, and then tailoring to the application, such as to design a

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diagnostic test or therapeutic product for a specific disease or to reengineer a plant to fight off insects. But, along with rising numbers of CRISPR researchers, platform-like network effects and multisided market dynamics are also appearing and helping the ecosystem grow. In particular, more research publications have led to

…

researchers and applications, which in turn have inspired more research, tool development, applications, venture capital investments, and so on. An important player in the nascent CRISPR ecosystem is a nonprofit foundation called Addgene, founded in 2004 by MIT students. It funds itself by selling plasmids, small strands of DNA used in

…

laboratories to manipulate genes. Since 2013, it has been collecting and distributing CRISPR technologies to help researchers get started on their experiments.36 The Addgene tools library consists of different enzymes and DNA or RNA sequences useful to

…

identify, cut, edit, tag, and visualize particular genes.37 There are also numerous start-ups, some of which have already gone public. CRISPR Therapeutics (founded in 2013) is trying to develop gene-based medicines to treat cancer and blood-related diseases, and is collaborating closely with Vertex and

…

) and Exonics Therapeutics (2017) are tackling diseases such as cancer, sickle cell anemia, muscular dystrophy, and cystic fibrosis.38 Beam Therapeutics (2018) plans to use CRISPR to edit genes and correct mutations.39 Mammoth Biosciences (2018) is following more of a platform strategy and developing diagnostic tests that could be the

…

licensing its patents and encouraging other firms to explore therapies based on its testing technology.40 In fact, Mammoth’s goal is to create “a CRISPR-enabled platform capable of detecting any biomarker or disease containing DNA or RNA.” In a recent public statement, the company summarized its strategy to cultivate

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Mammoth—bring affordable testing to everyone. But even beyond healthcare, we’re aiming to build the platform for CRISPR apps [italics added] and offer the technology across many industries.41 Broad commercialization of CRISPR is still years away. The technology is also better at screening, cutting, and rewriting rather than inserting DNA

…

.42 And only recently have medical centers and companies applied to start CRISPR-related clinical trials. There are also alternative technologies with different strengths and weaknesses. In particular, TALEN (transcription activator-like effector nuclease), another gene-cutting enzyme

…

tool, seems to be more precise than CRISPR and more scalable for some non-laboratory applications, though it can be more difficult to use.43 In general

…

, CRISPR is in the lead as a potential gene-editing technology platform, with several universities and research centers, start-up companies, and established firms actively publishing

…

papers, licensing and applying for patents, and sharing their tools and depositories of genetic components. Most researchers are also focusing on CRISPR-Cas9, a specific protein that used RNA to edit DNA sequences. One concern we have is that the business models of biotech start-ups and

…

which we saw in the early days of the personal computer, Internet applications, and even smartphone platforms such as Google’s Android. Of course, most CRISPR scientists openly shared and published their basic research.44 And although the U.S. Patent and Trademark Office already has granted hundreds of patents related

…

to CRISPR, patent holders usually offered free licenses to academic researchers, even those still under litigation. Ethical and social issues might also hinder widespread use of gene

…

editing, especially if more “rogue” and potentially dangerous misuses of CRISPR occur. The debates are clearly more serious than what we discussed in Chapter 6 regarding the abuse of social media platforms. The broader controversy involving

…

CRISPR centers on how much genetic engineering we, as a society, should allow. Experts already disagree about the safety of genetically altered plants and animals that

…

safely, and what types of government monitoring and self-regulation are most appropriate. These issues seem likely to become even fiercer topics of debate as CRISPR and other gene-editing technologies evolve into more widely used platforms for medical, food, and other applications. Final Thoughts Industry-wide platforms and global ecosystems

…

to Samantha Zyontz, a Ph.D. student at the MIT Sloan School of Management, for her assistance in understanding and writing up this discussion of CRISPR. We also acknowledge assistance from Gigi Hirsch and David Fritsche of the MIT Center for Biomedical Innovation. 32.Carl Zimmer, “Breakthrough DNA Editor Born of

…

Bacteria,” Quanta, February 6, 2015. 33.McKinsey & Company, “Realizing the Potential of CRISPR,” January 2017, https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/realizing-the-potential-of-crispr (accessed June 6, 2018). 34.Michael Specter, “How the DNA Revolution Is Changing Us,” National Geographic, August

…

2016. 35.Gina Kolata and Pam Belluck, “Why Are Scientists So Upset About the First Crispr Babies?” New York Times, December 5, 2018. 36.Samantha

…

Zyontz, “Running with (CRISPR) Scissors: Specialized Knowledge and Tool Adoption,” Technological Innovation, Entrepreneurship, and Strategic Management Research Seminar, MIT Sloan School of Management

…

, October 22, 2018. 37.See AddGene, “CRISPR Plasmids and Resources,” https://www.addgene.org/crispr/ (accessed October 19, 2018). 38.See Antonio Regalado, “Start

…

-up Aims to Treat Muscular Dystrophy with CRISPR,” MIT Technology Review, February 27, 2017; and Editas Medicine, “Our Pipeline,” http://www

…

.editasmedicine.com/pipeline (accessed June 14, 2018). 39.Amirah Al Idrus, “Feng Zhang and David Liu’s Base-Editing CRISPR Start-up Officially Launches with $87 Million,” FierceBiotech.com

…

, May 14, 2018. 40.Kashyap Vayas, “New CRISPR-based Platform Could Soon Diagnose Diseases from the Comfort of Your Home,” Science, April 29, 2018; and

…

Megan Molteni, “A New Start-up Wants to Use CRISPR to Diagnose Disease,” Wired, April 26, 2018. 41.“CRISPR Company Cofounded by Jennifer Doudna Comes Out of Stealth Mode,” Genome Web, April 26, 2018, https://www.genomeweb.com/business-news

…

/crispr-company-cofounded-jennifer-doudna-comes-out-stealth-mode#.WxgKnVVKicM (accessed June 6, 2018). 42.David Cyranoski, “CRISPR Alternative Doubted,” Nature, August 11, 2016, 136–37. 43.Labiotech editorial team, “The Most Important Battle in

…

Gene Editing: CRISPR Versus TALEN,” Labiotech, March 13, 2018, https://labiotech.eu/features/crispr-talen-gene-editing/ (accessed October 22, 2018); and Michael Boettcher and Michael T. McManus, “Choosing the Right Tool for the Job: RNAi

…

, TALEN, or CRISPR,” Molecular Cell 58, no. 4 (May 21, 2015): 575–85, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441801/ (accessed October 23, 2018). 44.Eric

…

Lander, “The Heroes of CRISPR,” Cell, January 14, 2016. 45.Carl Zimmer, “What Is a Genetically Modified Crop? A European Ruling Sows Confusion,” New York Times, July 27, 2018. 46

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, 109–10 content providers, 16, 73–74, 98 conventional companies. See traditional business core products and coring, viii, 72–73, 76, 253n12 CRISPR (innovation platform for gene editing), 229–34 CRISPR Therapeutics, 232 cross-side or indirect network effects, 17, 42–44, 46–47, 94–96 cryptocurrencies, 9, 111 Culp, Larry, 168

…

also barriers to entry; differentiation and niche competition; multi-homing; multisided markets; network effects platform potential and future scenarios, 217–37 overview, 28, 217–20 CRISPR, 229–34 quantum computing, 226–29 voice recognition, 220–23 Platform Revolution (Parker, Van Alstyne, and Choudary), 82–83 platforms, four steps to building, 66

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