The code breaker, p.19
The Code Breaker, page 19
Until then, she had rarely gotten sick. But now, in the summer of 2013, she found herself being hit with waves of pain and fever. Her joints locked up in the morning, and sometimes she could barely move. She went to a few doctors, who speculated that she might have a rare virus or perhaps an autoimmune condition.
The problems receded after a month, but then they recurred on a trip to Disneyland with her son late in the summer. “It was just the two of us, and each morning I’d wake up in our hotel and everything was hurting,” she recalls. “I didn’t want to wake up Andy, so I would go in the bathroom, close the door, and get on the phone with these people in Boston.” The stress of the situation, she realized, was affecting her physically.8
Nevertheless, she was able to reach an agreement with the Bostonmen by the end of the summer. A group coalesced with Doudna, Zhang, and Church at its core. Some Boston-based investment firms—Third Rock Ventures, Polaris Partners, and Flagship Ventures—provided commitments for more than $40 million in initial funding. The group decided to have five scientific founders, so they added two top Harvard biologists who had been working on CRISPR, Keith Joung and David Liu. “It seemed like the five of us were pretty much a dream team,” says Church. Their board included representatives from each of the three major investment firms along with some distinguished scientists. There was general consensus about most members, but Church did end up vetoing the selection of Eric Lander.
In September 2013, Gengine, Inc. was founded. Two months later, it changed its name to Editas Medicine. “We have the ability to essentially target any gene,” said Kevin Bitterman, a principal at Polaris Partners who served as the interim president for the first few months. “And we have in our crosshairs any diseases with a genetic component. We can go in and fix the error.”9
Doudna quits
After only a few months, Doudna’s discomfort and stress began to resurface. She sensed that her partners, especially Zhang, were doing things behind her back, and her qualms worsened at a January 2014 medical conference hosted in San Francisco by J.P. Morgan. Zhang came out from Boston with some of the management team from Editas, and they invited Doudna to a couple of meetings with potential investors. She got bad vibes as soon as she walked in. “I could immediately tell from Feng’s behavior and body language that something had changed,” she says. “He wasn’t collegial anymore.”
As she watched from a corner, the men at the meeting clustered around Zhang and treated him as the principal. He was introduced as “the inventor” of CRISPR gene editing. Doudna was treated as a secondary player, one of the scientific advisors. “I was being cut out,” she says. “There were things involving the intellectual property and I wasn’t being kept informed. There was something afoot.”
Then she was hit with a surprising piece of news, one that made her understand why she had the queasy sense that Zhang was keeping her in the dark. On April 15, 2014, she received an email from a reporter asking for her reaction to the news that Zhang and the Broad had just been granted a patent for the use of CRISPR-Cas9 as an editing tool. Doudna and Charpentier still had a patent application pending, but Zhang and the Broad, who had put in their own application later, had paid to have their decision fast-tracked. Suddenly it became clear, to Doudna at least, that Zhang and Lander were trying to relegate her and Charpentier to minor players—both in history and in any commercial use of CRISPR-Cas9.
It dawned on Doudna that this was why Zhang and many of the others folks at Editas had seemed secretive with her. The finance people in Boston had been positioning Zhang as the inventor. “They’ve known about this for months,” she said to herself, “and now this patent has been issued and they’re trying to completely cut me out and stab me in the back.”
It wasn’t just Zhang, she felt. It was the gang of men who dominated the biotech and finance world of Boston. “All the Boston people were all so interconnected,” she says. “Eric Lander was on an advisory board for Third Rock Ventures, and there was equity going back to the Broad from Editas, and there’s licensing agreements that can make them tons of money as long as Feng is seen as the inventor.” The episode made her physically ill.
In addition, she was exhausted. She had been flying to Boston once a month for meetings at Editas. “It was brutal. I’d buy an economy class ticket, sit straight up for five hours, and then get in at seven in the morning. I’d go to the United Club, take a shower, change my clothes, go to Editas, have our meetings, and then I’d often go to Church’s lab to talk about science. Then I would jump on a six p.m. flight back to California.”
So she decided to quit.
She talked to a lawyer about how to extract herself from the agreement she had signed. It took a little time, but by June they had drafted an email to the CEO of Editas saying that she was resigning. They finalized the text over the phone when she was at a meeting in Germany. “Okay, it’s ready to go,” the lawyer told her after they wrestled with a few final changes. It was evening in Germany and afternoon in Boston when she hit the Send button. “I wondered how many minutes it would be until my phone would ring,” she says. “It was less than five minutes, and it was the Editas CEO calling.”
“No, no, you can’t go, you can’t leave,” he said. “What’s wrong? Why are you doing this?”
“You know what you did to me,” she replied. “I’m done. I’m not going to work with people I can’t trust, people who stab you in the back. You stabbed me in the back.”
The Editas CEO denied being involved in Zhang’s patent filings. “Look,” Doudna replied, “you may be right or you may be wrong, but either way I can’t be part of this company anymore. I’m done.”
“What about all your stock?” he asked.
“I don’t care,” she shot back. “You don’t understand. I’m not doing it for the money. And if you think I’m doing it for the money, you don’t understand me at all.”
When Doudna recounted the episode to me, it was the first time I had heard her so angry. Her steady tone had disappeared. “He claimed he didn’t know what I was talking about, and it was ridiculous. It was bullshit. It was all a bunch of lies. And I could be wrong, Walter, but that was my feeling about it.”
* * *
All of the founders of the company, including Zhang, sent her emails that day asking her to reconsider. They offered to make amends and do whatever was possible to heal the rift. But she refused.
“I’m done,” she emailed back.
Immediately, she felt better. “It suddenly seemed like this big weight came off my shoulders.”
When she explained the situation to Church, he suggested that, if she wanted, he would consider quitting as well. “I had had a phone call with George at his house on a Sunday,” she says. “He vaguely offered to step down, but then he decided not to, and that was his decision.”
I ask Church whether Doudna was right to mistrust the other founders. “They were conspiring behind her back, filing for patents without telling her,” he agrees. But he says that Doudna should not have been surprised. Zhang was acting in his self-interest. “He probably had lawyers telling him what to do and say,” says Church. “I try to understand why people do things.” Everyone’s actions, including those of Zhang and Lander, could have been predicted, he believes. “Everyone did what I would have expected them to do.”
So why didn’t he quit? I ask. He explains that it was not logical to be surprised by their behavior, so it was not logical to quit because of it. “I almost left with her, but then I thought, what would that accomplish? It would reward them by giving them the rest of the profits. I always advise people to stay calm. After I thought about it for a while, I decided it was better to be a little calm. I wanted to see a company succeed.”
* * *
Shortly after she left Editas, Doudna was at a conference where she explained what happened to Charpentier. “Oh, that’s interesting,” Charpentier responded. “Would you like to get involved with CRISPR Therapeutics?” That was the company that she had founded with Novak.
“You know, it’s like getting a divorce,” Doudna replied. “I’m not sure I want to get involved again right away. I’m kind of done with companies now.”
Within a few months, she decided that she would be most comfortable working with her trusted partner and former student Rachel Haurwitz, with whom she had started Caribou Biosciences in 2011. Caribou had created a spinoff called Intellia, with the mission of commercializing CRISPR-Cas9 tools. “I became very interested in 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 were the people who do good science but are more importantly honorable straight-shooters.”10
As a result, the pioneers of CRISPR-Cas9 ended up in three competing companies: CRISPR Therapeutics, founded by Charpentier and Novak; Editas Medicine, which included Zhang and Church and Doudna until she resigned; and Intellia Therapeutics, founded by Doudna, Barrangou, Sontheimer, Marraffini, and Haurwitz.
CHAPTER 29 Mon Amie
Drifting apart
Doudna’s decision to go with a competing company reflected, and perhaps contributed to, the slight coolness that had developed between her and Charpentier. She had tried hard to maintain their relationship. For example, when they first started working together, one of their goals was to crystallize Cas9 and determine its exact structure. After Doudna and her lab succeeded in doing so in late 2013, she asked Charpentier if she wanted to be a coauthor on the resulting journal article. Charpentier, feeling it was a project she had brought to the Doudna Lab, responded that she would like that. This annoyed Jinek, but Doudna went along. “I was really trying to bend over backwards to be generous to her,” she says, “and, frankly, I wanted to maintain our scientific and personal relationship.”1
Partly as a way to keep their scientific partnership intact, Doudna suggested to Charpentier that they coauthor a review article for Science in 2014. Unlike a “research article,” which is a featured paper on a new discovery, a “review article” is a survey of recent advances on a particular topic. Theirs was titled “The New Frontier of Genome Engineering with CRISPR-Cas9.”2 Doudna wrote a draft, and Charpentier made some edits. It helped to paper over, so to speak, any rift that might be developing between them.
Nevertheless, they began drifting apart. Rather than join Doudna in the quest to find ways to use CRISPR-Cas9 in humans, Charpentier told her that she planned to focus on fruit flies and bacteria. “I like basic research more than looking for tools,” she says.3 There was another underlying reason for the strain: from Doudna’s perspective, she was an equal co-discoverer of the CRISPR-Cas9 system, but Charpentier viewed CRISPR-Cas9 as her own project, one that she had brought Doudna into late in the game. At times she spoke of it as “my work” and referred to Doudna as if she were a secondary collaborator. Now Doudna was basking in the limelight, giving interviews and making plans to pursue new CRISPR-Cas9 studies.
Doudna never quite understood Charpentier’s proprietary feelings and couldn’t figure out how to deal with the coolness that was evident beneath her warm and insouciant manner. She kept suggesting ways they could work together, and Charpentier would reply, “That sounds great.” But then nothing would happen. “I wanted to continue collaborating, and Emmanuelle clearly didn’t,” Doudna says with sadness in her voice. “She never came out and said that to me. We just drifted apart.” Eventually, Doudna became frustrated. “I came to feel that it was a passive-aggressive way of interacting,” she says. “It was frustrating and it was hurtful.”
Part of their problem was the different levels of comfort each had with publicity. When they met at awards ceremonies or conferences, the interactions could be awkward, especially at photo sessions where Charpentier exuded a subtly condescending and amused attitude when the limelight focused on Doudna. Eric Lander, Doudna’s occasional antagonist at the Broad Institute, told me that when he talked to Charpentier she expressed resentment at the publicity Doudna got.
Rodger Novak saw Doudna as an American comfortable with acclaim, and his friend Charpentier, whose reputation he protected, as a more properly reticent Parisian. He pushed Charpentier to do more interviews and even get training in how to deal with the media. “It’s just a different style of an individual not being on the West Coast but being European, a French person, who focuses more on science than on media hype,” he later said.4
That is not fully accurate. Although she was comfortable with being a public figure and flattered by recognition, Doudna was not, in fact, someone who actively sought celebrity. She made a point of trying to share the limelight and prizes with Charpentier. Rodolphe Barrangou puts more of the blame on Charpentier. “Emmanuelle makes people feel uncomfortable, even when it comes time to pose for pictures or to be in a green room before a public appearance,” he says. “It’s baffling to me her lack of desire to share credit with others. I watch Jennifer try to share the light and even overcompensate, but Emmanuelle will seem slightly recalcitrant and resistant.”5
Their difference in style was reflected in many ways, including their musical tastes. At one of the award ceremonies they attended together, they each got to choose the song that would play when they went onstage. Doudna chose Billie Holiday’s bluesy rendition of “On the Sunny Side of the Street.” Charpentier selected a technopunk piece from the French electronica duo Daft Punk.6
* * *
One substantive issue that came between them is one that historians know all too well. Almost every person in any saga tends to remember their own role as being a little more important than the other players see it. That’s true in our own lives. We recall vividly the brilliance of our own contributions to a discussion; we’re a bit hazier when recalling the contributions of others, or we tend to minimize their significance. As Charpentier views the CRISPR narrative, she was the one who first worked on Cas9, identified its components, and then brought Doudna into the project.
Take, for example, the pesky little issue that keeps cropping up in this tale of the ongoing role of tracrRNA, which not only helps to create the crRNA that guides to a targeted gene but then also, as Doudna and Charpentier revealed in their 2012 paper, sticks around to help the CRISPR-Cas9 complex cleave the targeted DNA. After they published the paper, Charpentier would occasionally suggest that she knew about the ongoing role of tracrRNA back in 2011, before she started collaborating with Doudna.
This began to annoy Doudna. “If you look at talks that she’s given recently and the slides she has shown, my opinion is that she’s been coached by lawyers and is trying to present the work as if they already knew that the tracrRNA was important for Cas9’s function before we started our collaboration, and I think that’s disingenuous, it’s untrue,” Doudna says. “I don’t know whether that was her doing or coaching by lawyers, but I think she kind of tried to blur the line between what she did in her 2011 paper and what was figured out much later.”7
When I ask Charpentier over dinner about the coolness that has developed between them, she is circumspect. She knows, after all, that I am writing a book with Doudna as the central character, and she has never tried to persuade me to shift my focus. With a dash of indifference, she admits that her March 2011 Nature paper did not, in fact, describe the full role of the tracrRNA, but she laughs and adds that Doudna should relax a bit and not be so competitive. “She doesn’t need to be so stressed about getting proper credit for the tracrRNA and things,” Charpentier says. “I find it unnecessary.” She smiles as she describes Doudna’s competitive streak, as if she finds that trait both admirable and amusing, but also faintly indecorous.
Their rift was exacerbated in 2017 when Doudna published a book on her CRISPR work, coauthored with Sam Sternberg, that was judicious but tended to use the first person more than Charpentier thought was seemly. “It’s written in the first person even though her student did most of the writing,” Charpentier says. “He should have been told to write in the third person. I know people who do the prizes and the Swedish mentality. They don’t like people to write books too early on.” By putting the words “prizes” and “Swedish” in the same sentence, she was referring to the most famous of them all.
Prizes
One force that kept Doudna and Charpentier bonded was scientific prizes. Their chances for winning them were best as a pair. Some carry awards of $1 million or more, but they have an even more important value than the money. They serve as a scorecard that the public, press, and future historians use to decide who deserves the most credit for important advances. Lawyers even cite them in arguments made in patent cases.
Each important science prize is given to a limited number of people (for the Nobel, the maximum is three in each field), so the awards do not reflect the full cast of players who contributed to a discovery. As a result, they can distort history and be a disincentive to collaboration, just like patents.
One of the largest and most glamorous of these awards, the Breakthrough Prize in Life Sciences, was given to Doudna and Charpentier as a pair in November 2014, a few months after Zhang beat them to the first patents. The citation heralded them “for harnessing an ancient mechanism of bacterial immunity into a powerful and general technology for editing genomes.”
The prize, which carries a $3 million award for each recipient, had been established a year earlier by the Russian billionaire and early Facebook funder Yuri Milner, along with Sergey Brin of Google, Anne Wojcicki of 23andMe, and Mark Zuckerberg of Facebook. Milner, an ebullient fanboy of scientists, staged a glittering televised award ceremony that infused the glory of science with some of the glamor of Hollywood. The 2014 black-tie event, cohosted by Vanity Fair, was held in a spacecraft hangar at NASA’s Ames Research Center in Mountain View, California, in the heart of Silicon Valley. The emcees included actors Seth MacFarlane, Kate Beckinsale, Cameron Diaz, and Benedict Cumberbatch. Christina Aguilera performed her hit “Beautiful.”
