The Doudna-Charpentier Science paper was the impetus for several groups to demonstrate CRISPR-Cas gene editing in living cells. Doudna was at an initial disadvantage. Her specialty was RNA and structural biology, not cell biology and human genetics. Other groups clearly had the edge in expertise and materials. But Jínek was optimistic. After all, researchers had succeeded in using bacterial DNA-cutting enzymes at the heart of the ZFN and TALEN systems. Some engineering would definitely be required—adding a nuclear localization signal to ferry the Cas9 complex into the nucleus, and making some subtle changes to the DNA sequence (a process called codon optimization) to better fit a mammalian cell. But a priori, Jínek reckoned there was “nothing fundamentally different or any impediment to getting it to work in mammalian cells.”
On October 3, Doudna’s inbox chimed with a message that supported Jínek’s belief. The sender was Jin-Soo Kim, a leading molecular biologist in South Korea. His lab had been pursuing CRISPR editing since Doudna and Charpentier’s “seminal paper” and was preparing to submit a new report on “Genome editing in mammalian cells.” Kim generously asked if Doudna (and Charpentier) would be interested in publishing together. “I do not wish to scoop you because your Science paper prompted us to start this project,” Kim wrote. But he wasn’t interested in getting scooped, either.22
Six weeks later, Church likewise emailed Doudna and Charpentier “a quick note to say how inspiring and helpful” he had found their CRISPR paper. “I’m sure you have received similar appreciative comments from other labs.”23 Church divulged that he was trying to get CRISPR working in human stem cells, only adding to the stiffening competition. Doudna felt the pressure of growing demands and responsibilities. “My inbox was exploding and journal editors were calling me,” she recalled. “It was just crazy. You could see this tidal wave coming toward you.”24
Jínek worked diligently in his final few months in Doudna’s lab to prove his hunch. On December 15, 2012, Doudna and Jínek sent their latest manuscript to the online journal eLife, funded in part by HHMI. The rhetorical question posed in the opening of their paper—could the bacterial Cas9 system work in eukaryotic cells?—had been answered in the affirmative. Given the evident competition from Church, Kim, and who knows who else, Doudna was hoping for a quick decision. She got it. On January 3, 2013, the eLife editor emailed her to say her paper had been accepted. Both referees, one of whom revealed himself to be Dana Carroll, loved the work. The editor called the manuscript “excellent” and concluded that the ease of programmability meant that CRISPR would probably supplant ZFNs and TALENs for genome editing. Doudna’s results would “likely have a transformative impact in the field of genome engineering for human and many other species with complex genomes.”25
But Doudna’s delight was short-lived. That afternoon she received another emaiclass="underline" 26
Greetings from Boston and happy new year!
I am an assistant professor at MIT and have been working on developing applications based on the CRISPR system. I met you briefly during my graduate school interview at Berkeley back in 2004 and have been very inspired by your work since then.
Our group in collaboration with Luciano Marraffini at Rockefeller recently completed a set of studies applying the type II CRISPR system to carry out genome editing of mammalian cells. The study was recently accepted by Science and it will be publishing [sic] online tomorrow. I have attached a copy of our paper for your review.
The Cas9 system is very powerful and I would love to talk with you sometime. I am sure we have a lot of synergy and perhaps there are things that would be good collaborate [sic] on in the future!
Very best wishes,
Feng
The Boston bombshell came from Feng Zhang at the Broad Institute. Just like the double helix, the story of CRISPR genome editing has a complementary strand, the twists and turns of which are still being unraveled.
I. Cool’s scope of articles read: “Cool only publishes articles that it deems to be astonishingly cool beyond belief. Any dorky shit submitted will be returned immediately to the authors postage due; there is just too much cool shit submitted (mostly by Cool Dudes) to waste our precious thick glossy sexy stock on it.”
II. Scientists do love to trot out Isaac Newton’s famous quote about “standing on the shoulders of giants” to acknowledge the scientific contributions of their colleagues and predecessors, although there is a school of thought that says Newton was actually trolling his diminutive rival, Robert Hooke.
CHAPTER 6 FIELD OF DREAMS
One could say that Feng Zhang’s immigrant story—from China to Iowa, Harvard to Stanford, back to Harvard, to MIT, 60 Minutes and scientific celebrity, fame, and a fortune in the making—is the quintessential American Dream. In 1993, Shujun Zhou, a Chinese computer engineer, brought her eleven-year-old son from Shijiazhuang, a heaving city of 10 million people about 150 miles southwest of Beijing, to the United States. They settled in Des Moines, Iowa—a world apart from his bustling birthplace. Driving around the Hawkeye state, Zhang would see a relentless landscape of cornfields and cattle, and highways lined with religious billboards with uplifting signs such as “After you die, you will meet God.” The car radio might have picked up the “Bible Bus,” a twenty-four-hour Christian station. His new home was indeed “a lot more ‘Zen-like,’ a lot more calm,” Zhang jokes. Compared to his home, Des Moines felt “empty.”
Zhang enrolled in the Callanan Middle School and soon became fluent in English. He got his first taste of molecular biology in eighth grade during a Saturday afternoon enrichment program. He joined a group of fellow nerdy middle school students called STING—Science and Technology in the Next Generation, inspired by Star Trek, organized by Ed Pilkington. The first documentary he watched, he jokes, was Steven Spielberg’s Jurassic Park, which for all the revisionist criticism of Michael Crichton’s dinosaur-DNA-locked-in-amber premise, inspired Zhang to imagine the possibilities of engineering and programming biological systems.
Zhang didn’t know it, but Crichton’s storyline gave rise to one of the first documented accounts of genome editing. In his original novel, Crichton included an excerpt of DNA sequence purported to represent dinosaur DNA. But when bioinformatician Mark Boguski idly typed the sequence into his computer, he was crushed to find that Crichton’s dino-DNA actually belonged to a bacterium. After Boguski busted Crichton in a short essay,1 Crichton contacted Boguski offering both an apology and an invitation to supply a more fitting sample for the sequel. Boguski chose a segment of chicken DNA, representing a living dinosaur descendant, which Crichton included in The Lost World. What the novelist didn’t know was that Boguski had left an easter egg in the sequence: when the genetic code was translated into its corresponding amino-acid code,I there were four small insertions that, taken together, read: