The code breaker, p.18
The Code Breaker, page 18
Jinek, however, was reluctant to rush their paper into print. “He’s a real perfectionist, and he wanted to have a lot more data, a bigger story,” she recalls. “He felt what we had wasn’t worth publishing.” They had many heated discussions, including one in the Berkeley quad in front of their lab in Stanley Hall.
“Martin, we have to publish this, even if it’s not quite the story we wish we could tell,” Doudna said. “We have to put out the best story that we can, with the data that we have, because we don’t have any more time. These other papers are coming out and we have to publish.”
“If we publish this work, we’re going to look like amateurs in the genome editing field,” Jinek shot back.
“But Martin, we are amateurs, and it’s okay,” she replied. “I don’t think people are going to think badly of us. If we had six more months, we could do a lot more, but I think you will understand better as time goes by that it’s incredibly important for us to publish this right now.”2
Doudna recalls that she “put her foot down,” and after a bit more discussion they came to an agreement: Jinek would put together the data and figures for the experiments, but Doudna would have to write the paper.
At the time, she was working on revising a second edition of a textbook on molecular biology she had written with two colleagues.3 “We hadn’t been entirely happy with the first edition, so we rented a house in Carmel to have a two-day powwow on how to revise it,” she says. As a result, she found herself in mid-December in Carmel, where it was wickedly cold, in a house that had no working heat. The owners said they would call a repair person, but they couldn’t get anyone out there right away. So Doudna and her coauthors huddled around the fireplace as they worked late into the night revising their textbook.
After everyone went to bed at 11 p.m., Doudna stayed up to prepare her CRISPR paper for eLife. “I was exhausted and cold and I realized that I had to write the paper then or it wouldn’t get written,” she says. “So I sat up for three hours in bed, pinching myself to stay awake, and typed out the text of a draft.” She sent it off to Jinek, who kept coming back with suggestions. “I didn’t tell my textbook coauthors or editors about any of this, so you can imagine the scene where I’m in this freezing cold house trying to talk about this textbook but I’m totally distracted because I knew I had to get the paper written, and Martin kept coming back with revisions.” Finally, she cut Jinek off and declared the paper finished. On December 15, she emailed it to eLife.
A few days later, she and her husband, Jamie, and their son, Andy, left for a ski vacation in Utah. She spent a lot of her time in their room at the lodge as she negotiated little fixes with Jinek and pushed the eLife editor to speed up the reviewing process. Every morning she would check the Science magazine website to see if the Church or Zhang paper had been published. The main scholar who was doing the peer review of her paper was in Germany,4 and Doudna was prodding him by email almost daily.
She was also on the phone with her former collaborator Emmanuelle Charpentier, who was in Umeå, where it was now dark all day. “I was trying to manage my relationship with her, and I didn’t want her to feel that we had somehow cut her out of that story, but the reality was that she hadn’t participated in the science for the eLife paper,” Doudna says. “So we acknowledged her, but in the end she wasn’t a coauthor.” Doudna sent her a draft of the manuscript, hoping she would not be upset. “I’m fine,” Charpentier responded, without much elaboration. There was a certain frostiness. What Doudna did not quite understand was that, even though Charpentier had not wanted to collaborate on the effort to edit human cells, she felt a little proprietary about the CRISPR-Cas9 system. After all, she was the one who had brought Doudna in on that work when they met in Puerto Rico.5
When the peer-review coordinator in Germany finally got back with comments, he asked for a few additional experiments. “A few of the mutated targets must be sequenced, just to demonstrate that the expected types of mutations are present,” he wrote. Doudna was able to brush him back. Doing the suggested experiments would “require analyses of close to a hundred clones,” she replied, which would “be better performed as part of a larger study.”6
She prevailed, and on January 3, 2013, eLife accepted her paper. But she couldn’t celebrate. The evening before, she had received, out of the blue, a happy-new-year 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 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 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 to collaborate on in the future!
Very best wishes, Feng
Feng Zhang, Ph.D.
Core Member, Broad Institute of MIT and Harvard
If Jinek had been less balky, I later ask Doudna, might her paper have been published sooner? Might she have been able to tie, or even beat, Zhang and Church, even though her team had finished their experiments after them? “It would have been tough,” Doudna says. “I don’t think so. We were still doing experiments right up until the very last minute because Martin, rightfully, wanted to make sure that the data included in the paper had been replicated three times. I wish it had been possible to submit earlier, but it probably wasn’t.”
Their paper did not have an extended version of the guide RNA, which both Zhang and Church showed worked better in human cells. Unlike Church’s paper, theirs also did not include templates for homology-directed repair that would create more reliable DNA edits. However, it did show that a lab specializing in biochemistry could quickly move CRISPR-Cas9 from a test tube to human cells. “We show here that Cas9 can be expressed and localized to the nucleus of human cells,” Doudna wrote. “These results demonstrate the feasibility of RNA-programmed genome editing in human cells.”7
* * *
Some great discoveries and inventions—such as Einstein’s theories of relativity and the creation of the transistor at Bell Labs—are singular advances. Others—such as the invention of the microchip and the application of CRISPR to editing human cells—were accomplished by many groups at around the same time.
On the same day that Doudna’s paper appeared in eLife, January 29, 2013, a fourth paper was published online showing that CRISPR-Cas9 worked in human cells. It was by a South Korean researcher, Jin-Soo Kim, who had been corresponding with Doudna and credited her June 2012 paper for laying the ground for his own work. “Your Science paper prompted us to start this project,” he had written in a July email.8 A fifth paper published that day, by Keith Joung of Harvard, showed that CRISPR-Cas9 could genetically engineer the embryos of zebrafish.9
Even though Doudna had been beaten by a few weeks by Zhang and Church, the fact that five different papers on CRISPR-Cas9 editing in animal cells all appeared in January 2013 reinforced the argument that this discovery was inevitable after it had been shown that it could work in a test tube. Whether that was a difficult step, as Zhang contends, or an obvious step, as Doudna claims, the idea of using an easily programmed RNA molecule to target specific genes and change them was, for humanity, a momentous step into a new age.
CHAPTER 28 Forming Companies
Square dances
In December 2012, a few weeks before the multiple papers on CRISPR gene editing were due to be published, Doudna arranged for one of her business associates, Andy May, to meet with George Church at his Harvard lab. An Oxford-educated molecular biologist, May was the scientific advisor at Caribou Biosciences, the biotech company that Doudna had started with Rachel Haurwitz in 2011, and he wanted to explore the business potential for using CRISPR-based gene editing as a medical technology.
Doudna was giving a seminar in San Francisco when May tried to reach her to report on the meeting. “Can we talk later tonight?” she texted back.
“Yes, but I really need to talk to you,” he responded.
When she reached him, she was driving back to Berkeley. He began by saying, “Are you sitting down?”
“Yes, of course, I’m driving home,” she replied.
“Well, I hope you don’t drive off the road,” he said, “because I had this incredible meeting with George who says this will be the most amazing discovery. He’s changing his entire gene-editing focus to CRISPR.”1
Rodger Novak, Jennifer Doudna, and Emmanuelle Charpentier
The excitement over the potential of CRISPR provoked all of the major players to begin square dancing, forming groups and swapping partners in the quest to create companies that would commercialize CRISPR for medical applications. Doudna and May decided, at first, to launch a company with Church and, if they could corral them, some of the other CRISPR pioneers. So in January 2013, Haurwitz accompanied May back to Boston for another meeting with Church.
Church’s bushy beard and cultivated eccentricities continued to make him a scientific celebrity, and on the day of the meeting that caused him to be distracted. In an interview with the German magazine Spiegel, he had offhandedly speculated about the possibility of resurrecting a Neanderthal by implanting its DNA in the egg of a volunteer surrogate mother. Not surprisingly (except perhaps to him), his phone rang nonstop as tabloid reporters jumped on the story.2 But he finally focused on his meeting, and within an hour they had a plan. They would try to enlist Emmanuelle Charpentier and Feng Zhang, along with a few top venture capitalists, into a grand consortium to commercialize CRISPR.
* * *
Charpentier, in the meantime, was working on a potential startup of her own. Earlier in 2012, she had contacted Rodger Novak, her onetime boyfriend and longtime scientific partner, whom she had befriended when they were researchers at Rockefeller University and in Memphis. They had remained close personal friends, and he had by then joined the pharmaceutical company Sanofi in Paris.
“What do you think about CRISPR?” she asked him.
“What are you talking about?” he replied.
But once he studied her data and consulted with some of his colleagues at Sanofi, he realized it would make sense to launch a business around it. So he called a close friend who was a venture capitalist, Shaun Foy, and they decided to discuss the prospect by going on a surfing trip (even though neither of them knew how to surf) off the northern part of Vancouver Island. A month later, after he had done some more due diligence, Foy called Novak and said they needed to launch a company as soon as possible. “You have to quit your job,” he told Novak, who eventually did.3
* * *
In the hope of getting all of the main players to coalesce, a brunch meeting was scheduled in February 2013 at The Blue Room, a once trendy restaurant with zinc-topped tables nestled in a renovated brick factory near MIT. It was located in Kendall Square in Cambridge, an epicenter of institutions that turn basic science into profitable applications: corporate research centers such as those of Novartis and Biogen and Microsoft, nonprofit institutes such as the Broad and the Whitehead, and a few federal funding agencies such as the National Transportation Systems Center.
Invited to the brunch were Doudna, Charpentier, Church, and Zhang. At the last minute Zhang canceled, but Church urged that they forge ahead without him. “We need to start a company because there is so much we can do with this,” he said. “It’s so powerful.”
“How big do you think it is?” Doudna asked him.
“Well, Jennifer, all that I can tell you is that there is a tidal wave coming,” he replied.4
* * *
Doudna wanted to work with Charpentier, even though they had been drifting apart scientifically. “I spent many hours on the phone with her trying to convince her to come along as a cofounder of what I was doing with George,” Doudna says. “But she really did not want to work with some of the folks in Boston. I think she didn’t trust them, and in the end I think she was right. But I didn’t see that at the time. I was trying to give people the benefit of the doubt.”
Church was not as eager to have Charpentier on board. “I became somewhat wary about joining forces with her,” he says. “One of the reasons we didn’t go in with her was because her boyfriend wanted to be CEO. We just felt that was a nonstarter. You needed to have a process by which you pick the CEO. I was willing to go with it. I tend to be accommodating. But Jennifer laid out the reasons against it, and I said, ‘Yeah, you’re right.’ ” (In fact, by then, Novak and Charpentier were no longer romantically involved.)5
Andy May had the same negative reaction when Doudna arranged for him to meet with Novak and Foy. “They came in pretty heavy-handed,” May says of Charpentier’s two business partners. “Their initial approach was that we should get out of the way and let them take care of it.”6
To be fair, both Novak and Foy had been involved in businesses and knew what they were doing. So along with Charpentier, they broke off discussions with the Doudna-Church group and instead founded a company of their own, CRISPR Therapeutics, initially based in Switzerland but later also in Cambridge, Massachusetts. “It was extremely easy to access money then, especially if you were called CRISPR,” Novak says.7
* * *
For a while in 2013, it seemed as if Doudna and Zhang, despite their rivalry, might become business allies or partners. After he missed the February 2013 brunch at The Blue Room, Zhang sent Doudna an email asking if she might like to collaborate on topics related to the brain, which had long been one of his interests. “I remember sitting at my desk here at my kitchen in Berkeley, seeing him on Skype,” she says.
He came out to San Francisco for a conference that spring and met Doudna at the Claremont Hotel in Berkeley. “I went to see her because I thought it was important to have some common alliance around the intellectual property so that you could make this a clean field for people to practice,” Zhang says. His idea was that Berkeley’s intellectual property and potential patents would be put into a pool with the Broad’s, which would make it easy for users to license the CRISPR-Cas9 system. Zhang thought Doudna liked the idea, so Lander phoned her to see if they could establish the framework for such a patent pool. “The next day Eric told me that my trip was productive,” Zhang says, “and he thought we had cemented the alliance.”
But Doudna had qualms. “I just didn’t get a good feeling from Feng,” she recalls. “He was not forthright. He was being cagey about when they had actually filed for patents. It didn’t sit well with me.”
So she decided to give an exclusive license of her intellectual property, which Berkeley managed in coordination with Charpentier, to her existing firm, Caribou Biosciences, and not do an alliance with the Broad. Zhang says that he thinks Doudna “has difficulty trusting people,” so she relied too heavily on her former student and Caribou cofounder Haurwitz. “Rachel is a nice person and smart, but not the right person to be the CEO of such a company,” he says. “Someone much more seasoned in terms of being able to develop the technology is really important.”
The decision not to pool the CRISPR-Cas9 intellectual property would pave the way for an epic patent battle. It also would end up hampering the easy and widespread licensing of the technology. “I think in retrospect, if I had to do it over again, I would have licensed it differently,” Doudna says. “When you have a platform technology like CRISPR, it’s probably a better idea to license it in a way that offers it as broadly as possible.” She had no expertise with intellectual property, and she was at a university that didn’t have much either. “It was kind of like the blind leading the blind,” she says.
Editas Medicine
Although she did not want to put her intellectual property into a pool with the Broad’s, Doudna was still open to becoming a partner in a CRISPR-focused company that would license both her potential patents and those of the Broad. So throughout the spring and summer of 2013, she traveled many times to Boston to dance with a rotating cast of investors and scientists, including Church and Zhang, who were trying to put together companies.
On one trip in early June, she went jogging one evening along the Charles River by Harvard, remembering her days there studying RNA under Jack Szostak. Back then she never thought that her research would lead to commercial ventures. It was not part of the ethos at Harvard. Now Harvard had changed, and so had she. If she wanted to have a direct impact on people, she realized that forming companies would be the best way to translate the basic science of CRISPR into clinical applications.
As the negotiations dragged on through the summer, the stress of figuring out how to form a company began to wear her down. So did flying between San Francisco and Boston every few weeks. Particularly difficult was having to choose between working with Charpentier or with Church and Zhang. “I couldn’t tell what the right decision was,” she admits. “A couple of people in Berkeley, colleagues that I trusted and had started companies in the past, were telling me to definitely work with the people in Boston, because they were better at business.”
