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

Nonfiction | Biography | Adult | Published in 2021

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Chapters 24-27Chapter Summaries & Analyses

Chapter 24 Summary: “Zhang Tackles CRISPR”

By 2011, Zhang had moved to the multidisciplinary Broad Institute at MIT and Harvard, founded by Eric Lander in 2004. Zhang carried his work on TALENs over from Church’s lab, but he was stymied by the fact that each TALEN took three months to engineer. Therefore, learning about CRISPR at the Broad Institute was a game changer for Zhang.

To develop CRISPR into a gene-editing tool for human cells, Zhang enlisted the help of Le Cong, his former protégé at Harvard. Zhang sensed the CRISPR race was heating up and requested Cong, still at Church’s lab at the time, to keep their project a secret. Cong subsequently moved to the Broad Institute and, on February 13, 2011, Zhang filed a memorandum of invention at the Broad Institute. However, Zhang’s memorandum did not describe an actual invention but the concept of using CRISPR as a gene-editing tool. Though Zhang meticulously documented his work on CRISPR, he did not make it public. By 2012, when Charpentier and Doudna published their paper, Zhang had not yet figured out the role of tracrRNA in the Cas9-CRISPR mechanism. Earlier that same year, Zhang had reached out to Luciano Marraffini for a potential collaboration. An enthusiastic Marraffini joined Zhang but later claimed that it was he who guided Zhang toward focusing on the Cas9 enzyme instead of trying out Cas1, Cas3, or other systems. Despite the claim, Marraffini and Zhang had a brief successful collaboration, with Zhang devising ideas about what could work in human cells, and Marraffini testing them in microbes.

Zhang’s work with Marraffini was not published until 2013, leading to a question that has troubled the Nobel Prize jury, patent jurors, and scientists alike: When did Zhang know about CRISPR-Cas9? According to Broad Institute founder Eric Lander, Zhang had isolated the “robust three-component system” by mid-2012, potentially testing it in mice and human cells. Zhang told Isaacson that seeing the Doudna-Charpentier paper in Science spurred him to publish his own findings, since he did not want to get scooped.

Chapter 25 Summary: “Doudna Joins the Race”

Sensing the competitive urgency around CRISPR, Doudna pushed her chief researcher Martin Jinek to find a way to use CRISPR for gene editing. The enterprise was buoyed in fall 2012, when Alexandra East, a graduate student experienced in working on human cells, joined Doudna’s lab. East, trained at the Broad Institute, was able to grow human cells and test ways to get Cas9 into the nucleus. Though East was unsure her data was showing results, Doudna knew that East had achieved “beautiful evidence of genome editing by Cas9 in the human cells” (191). To Doudna, getting CRISPR-Cas9 to work in human cells was not a huge new invention but more an adaptation of existing methods. However, sensing that other labs would push their own adaptations of CRISPR-Cas9 in human cells as a major discovery, Doudna readied her team’s findings for publication. Meanwhile, Jinek ran into a hurdle: The single-guide RNA he had engineered was not long enough to work in human cells.

Chapter 26 Summary: “Photo Finish”

As Zhang tested the idea of a single-guide RNA, he found a flaw in the version described in the Doudna-Charpentier paper from 2012. He engineered a longer version of the RNA that included a hairpin turn, which made it work far better in human cells. For Zhang, the discovery of this flaw and his reinvention was proof that working with living cells was better than in vitro experiments. Zhang also tagged the Cas9 enzyme with a nuclear localization sequence, enabling the large protein to penetrate the hard shell of the nucleus in human cells.

Additionally, he used a famous technique called “codon optimization” to make the CRISPR-Cas9 system work in human cells. Codons are three-letter snippets of DNA that direct the specific arrangements of amino acids. Since a variety of codons can code for the same amino acids, when trying to shift a gene-expression system from one organism to another, like from bacteria to a human, the codon optimization system switches to the codon that works best.

Zhang’s submission to Science (dated October 5, 2012) included all the above mechanisms and listed Shuailiang Lin and Luciano Marraffini as coauthors. The paper ended with the significant note that genome editing in mammalian cells had potentially powerful applications. George Church was shocked to learn about Zhang’s paper. Having mentored Zhang and Le Cong, Church felt betrayed that Zhang had kept his work secret, especially since Church had recently submitted his own findings on CRISPR-Cas9 to Science.

Church’s findings were submitted on October 26, 2012, and both his and Zhang’s papers were published online on January 3, 2013. Like Zhang, Church had used a nuclear localization sequence and codon optimization. His version of the single-guide RNA worked even better than Zhang’s. Additionally, Church provided a template for DNA repair after CRISPR Cas9 made its double-strand break.

Chapter 27 Summary: “Doudna’s Final Sprint”

In November 2012, Doudna and her team were still collating their results on CRISPR-Cas9 in human cells. When she learned that Church and Zhang had submitted papers on the technology to Science, Doudna requested a copy of Church’s manuscript and was deflated by the extensive research he had conducted. She asked if she should even submit her work for publication; Church said yes. Doudna found Church very supportive and collegial through the entire process.

After revisions, Doudna emailed her paper to eLife, a journal with a quick review process, on December 15. Though Doudna acknowledged Charpentier in the eLife paper, she didn’t list her as a coauthor since she felt Charpentier hadn’t participated in the science of getting CRISPR-Cas9 into human cells. When Doudna sent Charpentier a draft of the manuscript, Charpentier’s approval was brief and frosty. Doudna had failed to realize that Charpentier was protective of CRISPR-Cas9, since it was Charpentier who had brought the work to Doudna. Doudna’s paper was published in eLife on January 29, 2013. It did not have the extended version of the single-guide RNA that Zhang and Church had used, or Church’s template for DNA repair. However, it showed that a biochemistry lab could quickly move CRISPR-Cas9 from the test tube to human cells.

Chapters 24-27 Analysis

With chapter titles like “Doudna Joins the Race” and “Photo Finish,” Isaacson builds Chapters 24-27 as a thrilling, hard-fought race. Verbs like “tackle” and “sprint” abound in these chapters, lending the proceedings a sense of urgency and competition. Isaacson’s goal is to capture the twisting intricacies of the race and to present the work of science in all its unpredictable, driven glory. Since Watson’s Double Helix, with its flair for drama, is cited throughout the text as an inspiration for both Doudna and Isaacson, it is fitting that Isaacson’s narrative pays homage to that classic.

The text also acknowledges that determining the single truth about who deserves greater credit in developing CRISPR-Cas9 in animal cells is futile. Every player has their own version of events, which may be equally valid. All Isaacson and the reader can do is hear each side out, allowing every player to present their own version of the truth.

For Zhang, his work on CRISPR-Cas9 was more relevant than Doudna’s, since he was working with the living cells of mice and humans. Work completed in vitro has no meaning until it can be applied to living cells. Doudna claims the opposite: Since she could show how the CRISPR-Cas9 system worked in a test tube, it could be potentially be applied to human cells in the future. Both were right in their own way; Zhang’s cellular biology and Doudna’s biochemistry complement each other.

Then there is the question of whether Zhang knew about CRISPR-Cas9 in human cells in 2012, when Doudna and Charpentier published their paper. Since Zhang had not made his work public at that stage, this is impossible to ascertain. To complicate matters further, Shuailiang Lin would later claim that Zhang’s lab had not gotten CRISPR to cut into human cells by 2012; the Broad Institute dismissed Lin’s claims as disingenuous. Though Zhang’s notes from 2012 document that he was able to show that the CRISPR-Cas9 system works in mice cells, some scientists say he cherry-picked the data. Others, like Doudna, contend that he learned about the role of tracrRNA only from her 2012 paper. Zhang accepts that he did learn about designing a single-guide RNA from the Doudna-Charpentier paper, but he insists that the technology is not essential to the CRISPR-Cas9 system.

Another question that crops up around Zhang is why he kept his work a secret from Church. Additionally, the text ponders whether Le Cong’s involvement and secrecy was ethical, since he was still a graduate student at Harvard. Zhang asserts that he did tell Church about his work while out on a drive, but Church slept off while Zhang was talking. However, Church, who does suffer from narcolepsy, believes that even if this happened, Zhang should have kept him in the loop about his plans. Lander, on the other hand, believes that all the talk of narcolepsy is bunkum and Church only started his work on CRISPR-Cas9 after Zhang told him his own plans. By catching the multiplicity of tellings, Isaacson emphasizes that the truth is very difficult to pin down. Each narrator naturally has biases about which they are myopic. For instance, Church believes Le Cong’s secrecy about CRISPR was unethical though within the “bounds of science,” but he is overall appreciative of Doudna, who some accuse of stealing Virginijus Šikšnys’s thunder.

If anything, the chorus of voices around CRISR is useful because it reveals that the story has more than one hero. The story of CRISPR-Cas9 shows that while some scientific discoveries—like Einstein’s theories of relativity—are singular advances, others, like using CRISPR technology in human cells, are accomplished by many groups around the same time. This is apparent in the various papers published in winter 2012-2013: In addition to Doudna’s paper, South Korean researcher Jin-Soo Kim published a paper on CRISPR-Cas9 technology in human cells, and Keith Joung of Harvard submitted a paper showing that CRISPR-Cas9 could genetically engineer the embryos of zebrafish.