Using Crispr and the Cas9 protein, this scientist made the discovery of the century...which one?
In the very best invention stories, the tinkerer spends years toiling in obscurity before the big breakthrough. Jennifer Doudna’s story is like that. The 52-year-old biochemist grew up in Hawaii, studied at Pomona College and Harvard, and later joined the faculty at the University of California at Berkeley. While the rest of the scientific world seemed fixated on DNA, the blueprint of all biology, Doudna built detailed maps of RNA, which had long been thought of as the loyal foot soldier following DNA’s orders. Doudna was trying to figure out more precisely what role RNA plays in human genetics—the various ways it can actually control genes. For years, DNA remained the focus of most everyone else’s research. “I definitely had some sleepless nights,” she says, “just wondering, Is this the right decision, should I be doing this?”
Then one day in 2011, Doudna was approached at a conference by a French microbiologist named Emmanuelle Charpentier, who wanted to talk about a phenomenon called Crispr. Until then, most biologists understood Crispr, assuming they’d heard of it at all, to be an antiviral system found in bacteria. The bacteria used it to identify invading viruses and activate special proteins that would bind to the viral DNA and snip it out. No one had successfully found a plausible way to adapt and re-create that bacterial process in a more complex biological system—like a human being. Whoever could pull that off might be able to cure diseases, alter the genetic code, and even change the human species. It all sounded like science fiction, of course, until Charpentier told Doudna that Crispr seemed to interact with a protein called Cas9 in an extraordinary way.
The two decided to join forces, and one year later published a study detailing how they’d adapted the Crispr-Cas9 editing technique to not just cut but paste genes into any bacteria—that is, customize a bacterium’s DNA makeup along whichever lines they chose, with little fuss. The technique was enormously promising. Editing the human genome had been possible for a few years, but slowly, imprecisely, and with great difficulty. Crispr-Cas9 might eventually make it almost as straightforward as the search-and-replace feature of a word processor. What if one day, using Crispr, we could edit out Alzheimer’s, schizophrenia, or cancer? Soon, the two scientists were onstage with Cameron Diaz, accepting the Silicon Valley-funded $3 million Breakthrough Prize in Life Sciences. They were on everybody’s shortlist for the Nobel prize, their work hailed as the great biotech advancement of the century. “I couldn’t have predicted it,” Doudna says.
That’s a nice story, but there’s another. It’s about Feng Zhang, a 34-year-old molecular biologist at the Broad Institute of MIT and Harvard. Zhang was born in China and raised in Iowa, and he quickly became a star at Harvard and Stanford, where he was obsessed with finding the perfect way to reprogram human cells. “I’ve always been focused on genome editing,” he says. In 2011, the same year Doudna met Charpentier, Zhang attended a conference at the Broad Institute, in the same building as his lab, and heard a speaker offhandedly mention the Crispr immune system in bacteria. Zhang read everything he could find on the subject. He fixated particularly on a Canadian biologist’s 2010 paper noting the exceptional utility of the Cas9 protein.
Zhang spent months testing Cas9 enzymes, and was preparing to publish his findings in 2012, when Doudna and Charpentier’s paper came out. In Zhang’s paper, published a few months later, he showed how he’d successfully harnessed Crispr with Cas9 to edit a gene in a eukaryotic cell—that is, a cell with a nucleus. In the eyes of some, that distinction vaulted him ahead of Doudna and Charpentier. To edit a bacterial gene, the way Doudna had, was one thing; to actually monkey with the building blocks of humanity was another.
Every decade or so, a fundamentally new genetic technology comes along that could change everything. In the 1970s it was restriction enzymes, the tools for recombinant DNA, which turbocharged the development of new medicines and the tools of basic biological research. In the ’80s, the polymerase chain reaction revolutionized day-to-day molecular biology by making it much easier to quickly copy a piece of DNA thousands of millions of times, speeding the pace of medical research even further. In the ’90s, next-generation DNA sequencing pushed forward the study of the genome to a level once thought impossible. Now there’s Crispr, which could trounce them all.
The name, coined in 2002 by Spanish researcher Francisco Mojica, is short for clustered regularly interspaced short palindromic repeats (you can tell somebody really wanted to spell “Crispr”). Today it’s understood to be, potentially, a cheap and quick way to fix anything about a genetic code. “It’s almost as fundamental as the transistor,” says Andrew May, the chief scientific officer at Caribou Biosciences, a Crispr startup co-founded by Doudna in 2011. “If you think of DNA as the fundamental sort of software code that underpins the computer that cells are, you’re essentially programming those cells. You can target any piece of DNA and change it.”
In the popular imagination, Crispr has prompted alarmed speculation about eugenics, designer babies, and hubris worthy of Jurassic Park. The results may be able to change inheritable traits that could forever alter the nature of any species—not just mosquitoes, which a British company named Oxitec plans to tinker with in the Florida Keys using a gene-modifying technique that predates Crispr. Researchers in China have already tried out Crispr-Cas9 on human embryos. They never intended to implant the embryos in mothers and reported mixed success at best. Yet the attempt shook many in the scientific community. In June, a federal biosafety and ethics panel approved human trials of Crispr-Cas9 by a University of Pennsylvania team that has the backing of Napster co-founder and itinerant entrepreneur Sean Parker. Home hobbyists, meanwhile, are using Crispr to fiddle with yeast in petri dishes, splicing together who-knows-what. Harvard researcher George Church appears serious about a plan to use Crispr to bring back the woolly mammoth.
Nearer-term advances could change our lives in more welcome ways. Researchers around the world see Crispr’s precision as a perfect tool for curing single-gene illnesses like Duchenne muscular dystrophy, cystic fibrosis, and an inherited form of blindness called LCA 10. “There are 6,000 or so genetic diseases, and 95 percent of them don’t have any proved therapies,” says Katrine Bosley, chief executive officer of Editas Medicine, a Cambridge, Mass., Crispr startup. “In this day and age, we have a deep knowledge of the human genome and how to make genetic medicines that we didn’t have 5, 10 years ago.”
AstraZeneca and Novartis have teamed up with Crispr startups to develop and bring drugs to market. Beyond cures, Crispr is being viewed as a way to make cancer drugs more effective, to build a better class of antivirals to fight HIV, and to modify pig organs to make them more suitable as transplants for humans. In just a few years, the technique could make its way into everything from medicine to agriculture to biofuels—anything involving a gene. Imagine genetically modified crops that, with Crispr’s assistance, don’t use any genes other than their own, sidestepping the GMO controversy. DuPont is already working with Caribou on mushrooms that stay white after being cut, and told Doudna it has 25 Crispr-related products in the pipeline, including corn, soybeans, wheat, and rice.
For a time, Zhang and Doudna were cordial. Along with a few other molecular biologists, they joined the board of Editas. Then, in 2014, the federal government granted Zhang the first patent on Crispr-Cas9. Although Doudna and Charpentier enjoyed a wave of glowing press, Zhang stood to get the money and, maybe, the spot in the history books. Doudna left Editas a month later; though she says the reason was too many cross-country commutes for board meetings, she helped found a new startup, Intellia Therapeutics, that would be directly competing for venture capital. The race for funding was on. Bill Gates and Google Ventures were among the contributors to Editas’s $120 million Series B investment round—Gates is particularly enthusiastic about altering entire mosquito populations to stop malaria—and the company netted an additional $94.4 million in a February initial public offering. Intellia, in turn, raised $112.9 million when it went public in May. Charpentier’s Crispr Therapeutics has yet to go public but has raised $198 million in venture funding and has contracts with Bayer and Vertex Pharmaceuticals worth a combined $440 million. “All I can say is that we did it in my lab with Jennifer Doudna,” she told one reporter in 2014. “I am very confident that the future will clarify the situation.” All told, Crispr companies have attracted more than $1 billion of venture capital and other funding, even as credit for the technology and its relevant patent remain a matter of dispute.
Next came the litigation. In 2015, UC Berkeley’s lawyers filed a claim on behalf of Doudna with the U.S. Patent and Trademark Office, seeking to strip Zhang and the Broad Institute’s hold on Crispr-Cas9. Proceedings began this spring, but the most dramatic part is still to come. In November, Doudna and Zhang may have to take the stand, each asserting under oath that she or he deserves the patent for what may well be the biological advancement of our age. The stakes are sky-high. Billions of dollars in revenue. Control over entire industries yet to be born. And, perhaps, the future of human evolution.
“I’m really an outsider to the genome-editing field,” Doudna says. “Other folks, they’ve been in this field, whereas we’re coming at this from a very different point of view.” It’s late on a Friday afternoon at UC Berkeley, and Doudna, tall and thin and cheerfully focused, is seated in her office with a sweeping view of the campus, fiddling with a 3D-printed model of the Cas9 protein—a plastic toy, really, a bit larger than a football—that she keeps nearby to explain the Crispr technique to visitors. She still marvels at Crispr’s utility as “a democratizing technology. It just opens the door to anybody who has basic skills in molecular biology and wants to do some genome editing.” That includes those who might want to customize a newborn’s genes. Doudna has helped lead the effort to encourage ethical uses of Crispr, but she’s not for a complete moratorium on human experimentation. “On one hand, you can say maybe it’s not right to do that ever, but you can also say in vitro fertilization clinics already do that every day.” Her lab is working on curing the neurodegenerative disorder known as Huntington’s disease.
The only part of her Crispr story Doudna hesitates to comment on is the battle for credit. For two years, UC Berkeley and the Broad Institute have engaged in a simmering public-relations war over who invented the Crispr-Cas9 method, each spinning its version in press releases and video primers. For her part, Doudna says her work with RNA molecules made her research distinctive. Everyone else, she says, was looking at DNA. That would include Zhang. “What I’ve always found interesting in science,” she says, “is making connections between things that are not necessarily connected or don’t appear to be connected.”
“On one hand, you can say maybe it’s not right to do that ever, but you can also say in vitro fertilization clinics already do that every day"
Across the country, Zhang’s lab in Cambridge is at the Broad Institute in Kendall Square, the world nexus of biotech investment and research, a five-minute walk from Editas’s offices. When I visit a week after meeting with Doudna, Zhang greets me with a warm, confident smile. Boyish and upbeat, he’s eager to discuss his lab’s latest advances in Crispr techniques: the methods he’s found to make the editing more precise; his ambition to map out complex brain diseases like Alzheimer’s; the protein he found that works as well as Cas9 and which he owns the patent to, free and clear. If Doudna is an outsider to the gene-editing world, Zhang is a native, an Intel Science Talent Search finalist who’s been devoted to the idea of reprogramming DNA since 1993, when an after-school program in Des Moines took him to see Jurassic Park.
Unlike Doudna, who badly wants to shape the way the public thinks about Crispr, Zhang isn’t interested in ethical conversations about designer babies, which he says are a long way off. “The thing everybody should focus on is how we can push this technology forward, so we can actually treat a disease,” he says.
Zhang is as quietly focused as Doudna in asserting his ownership of Crispr. Without ever saying her name, he argues that her big Crispr paper with Charpentier didn’t actually scoop him, because they stuck with bacteria and used the Cas9 protein in a different way. “You have to test it in the actual system that you want to get it to work in,” he says. “Nothing else is going to be able to fully predict what will happen.”
The entire Harvard and MIT apparatus appears to have lined up behind Zhang’s version. In January, Eric Lander, president of the Broad Institute, published an elaborate history of Crispr in the journal Cell that spread credit around to a host of researchers over years. The effect, more than one Doudna supporter protested, was to vastly downplay her contribution. Amid the tempest that followed, Doudna called Lander’s article “factually incorrect.” Still, Lander’s broader point—that today’s discoveries are often an ensemble effort—does resonate with Doudna. “I wouldn’t disagree with that, yeah,” she says.
Does it follow, then, that the patent system should allow people to share credit? Doudna takes a moment before answering. “It’ll probably be a while,” she says, “before I have enough perspective that I can really answer that question.”
Many were surprised that Zhang received the Crispr-Cas9 patent, given that Doudna published first and filed for her patent seven months ahead of him. The reason: Zhang had paid $70 to have his application expedited. Some have interpreted that as a slimy move; the patent lawyers and experts I spoke with say that may have been his only option to avoid his application being deemed in conflict with Doudna’s. In any case, almost immediately after Zhang got his first patent on April 15, 2014, UC Berkeley amended Doudna’s application to counter his claim. Then a few third parties, their identities still not made public, filed briefs to block Doudna. The patent war had begun.
The Broad Institute produced lab notebooks and private e-mails to bolster its case that Zhang’s idea was original and that Doudna’s predictions that Crispr-Cas9 would work in humans was “mere conjecture.” UC Berkeley claimed Zhang’s notebooks were missing key information, going so far as to say the Broad Institute “withheld or misrepresented material information with the intent to deceive” the patent office. Preliminary meetings with a judge this spring generated more heat than light, and UC Berkeley’s objections failed to get any traction. Next, in what’s called the interlocutory phase, a panel of three patent judges will be handed the task of determining who invented Crispr-Cas9.
“The Berkeley lab is going to say they had the building blocks,” says Sarah Chapin Columbia, an intellectual-property litigator with McDermott Will & Emery in Boston. “The MIT-Harvard lab is going to say, ‘We put the building blocks in the right orientation.’ To a patent geek, that’s going to be a very interesting thing to watch.”
There’s one more major quirk. The entire dispute, called an “interference” case because the patent claims are said to interfere with one another, is moving forward based on a set of rules that have been changed since it was filed. Under the old rules, the scientist deemed the “first to invent” wins. Under the new rules, the patent goes to the “first to file,” matching the system in many other countries. The new system operates under the assumption that the early filer will be the best able to build an industry around the invention, says Kevin Noonan, a biotech patent expert and partner with law firm McDonnell Boehnen Hulbert & Berghoff in Chicago. “So these days we don’t care so much if the right person gets the patent,” he says. “It may not be more fair, but it’s simpler.”
Even if the current patent system encourages innovation, the rules hardly seem fair to the inventors—or true to the reality of invention itself. Does this process accurately reflect the way people from Thomas Edison and Nikola Tesla on down have tended to invent things in parallel? Science thrives when scientists share data and ideas, but the winner-take-all patent system almost forces scientists to guard their best stuff. And when patents are contested, the proceedings can be brutal. “Every piece of evidence has to be independently corroborated by somebody who swears under oath that it’s true,” Noonan says. “Too often, things can get shaded, because your recollections are not consistent with reality. Especially when having those recollections means you make a lot of money.”
The best thing you can say about the process, perhaps, is that it can motivate people to settle for some sort of cross-licensing arrangement. “That’s really the smart thing to do,” Noonan says. “If they settle, then they both win.” If one party wins, appeals could last years. There’s always the possibility the panel of judges will award the patent to neither party. And the longer they battle over the patent, the more risk to its licensing value. Zhang isn’t the only researcher trying to invent a way around this patent, finding proteins besides Cas9 that work with Crispr. The search is moving quickly: In June, the journal Science published a study showing how the technique could be used to manipulate not just DNA but RNA, too. And the patented version may well fail human clinical trials or face years of delays like gene therapy did after 1999, when one of the volunteers in a human trial died.
Yet an April filing in the case showed the parties have discussed settling and held off. For now, the various Crispr companies’ investors are holding tight. “We knew it was high-risk,” says Kevin Bitterman of Polaris Partners, the venture firm that helped form Editas with Flagship Ventures and Third Rock Ventures. “We did a lot of due diligence on the intellectual property and feel very confident in the company’s position.”
It’s not possible with any degree of certainty to pick the eventual winners. “Every investor in the Crispr space thus far is essentially betting on a horse race,” says Jacob Sherkow, a New York Law School professor who is following the dispute. “If you’re paying Caribou Biosciences for a license on their technology”—that is, the technology Caribou licensed from Doudna—“you’re essentially gambling on them winning. And if Caribou loses, then you never had to pay that money. But you know, it’s a transformational piece of technology. So it’s better to get in on it now than to wait. There’s that Warren Buffett quote—‘If you wait for the robins, spring will be over.’ ”
Patents might not be the most important front in the Crispr war. They’re good for only 20 years, after all; history is forever. The Nobel committee typically honors no more than three people per discovery, no matter how many actually worked on it. Doudna, Charpentier, and Zhang aren’t the only contenders: Media reports have also lauded Harvard’s Church, DuPont’s Philippe Horvath, and Rodolphe Barrangou of North Carolina State University for their work on Crispr.
“There’s a lot of competition,” Doudna says. “It’s true in any human endeavor. People get excited about an idea, and then a lot of people go after it.” She’s flattered but a little worried about the flurry of attention. “It would be so easy to get so distracted by all this stuff going on that I would never really do any real science again,” she says. “That’s actually my worst nightmare.”
Still, she knows the real advancements require money. “Is a cure for Huntington’s going to come from an academic lab?” she asks. “I mean, it’s just not going to. Do we have the resources to do clinical trials and all of the work to figure out really how to deliver this as a drug? No. That has to be done in a commercial setting.” So she’s embracing the commercial aspects of Crispr. “I want to see this used. I want to see it really solve real problems. I don’t care who does it, but if somebody has a cure for an eye disease or for a sickle-cell trait or for something like that, it’s going to be fantastic. That’s what I would love to see happen.”
Zhang is similarly fixated on perfecting the invention. “There’s so much hype around this, and there are so many things we have to work out,” he says. “How safe is the system in the body? How do we put it in the right organ? We have to work on resolving those questions. And all these other issues, they are really beside the point.”
How uncomfortable is it to be caught in the middle of a highly visible struggle over a major scientific legacy? “I didn’t start to work on this because I wanted to get a patent,” Zhang says. “If we can treat a disease, I mean, that’s what moves the world forward. It’s not patents or credit or anything like that.”
When I tell him Doudna says almost the same thing, he takes a long pause. Finally, he answers. “For me, I think the primary goal is to do something useful,” he says. “I think if you actually do something useful, you’ll get rewarded. The world will recognize the value you created, and the world will be a fair place.”
