DNA Wars in Cambridge

Three Cambridge biotech startups are vying for control of a revolutionary gene-editing tool called CRISPR-Cas9. On the line are a billion-dollar market, a potential Nobel Prize, and, yes, the power to resurrect an extinct species.
CRISPR-Cas9 Jennifer Doudna Feng Zhang Emmanuelle Charpentier

From left, Jennifer Doudna, Feng Zhang, and Emmanuelle Charpentier are vying for a Nobel Prize for their breakthrough work on CRISPR.

In nature, CRISPR is a sort of genetic defense system in bacteria, an ingenious way to defeat their mortal enemies. Viruses called bacteriophages attack bacteria by injecting their DNA. But CRISPR, a code written into many bacteria’s DNA, acts as a sentinel and a jailer: It recognizes and seizes the invading DNA. CRISPR’s daunting acronym is a description of those clever bacterial DNA strands. As researchers were studying how CRISPR worked, they noticed that one of the enzymes it creates—named Cas9—cuts virus DNA like molecular scissors. The method immediately raised the tantalizing possibility that CRISPR could be taken out of bacteria and used to edit human, animal, and plant DNA.

After learning of CRISPR, Zhang directed his lab to start working on CRISPR experiments right away, and spent much of 2011 and 2012 trying to edit human and animal genes. Using special human kidney cells and mouse cells, both rigged to glow under a microscope, he tried to send a CRISPR system into the nuclei to turn off the glow. If CRISPR could snuff out the light, that would mean it worked. Progress was slow but exciting: He’d peek under a microscope and see the glow fade a bit more each day.

Then, in June 2012, a new paper on CRISPR attracted frenzied interest. Berkeley’s Jennifer Doudna and European scientist Emmanuelle Charpentier published the most detailed explanation yet of how CRISPR systems worked, reporting that they could locate any DNA sequence they wanted to edit. Though they’d done their work in test tubes, and with non-animal cells, they speculated that CRISPR could potentially edit human genes.

At first, many people saw Doudna and Charpentier’s findings as a stunning discovery. Time magazine put the two scientists on its list of the 100 most influential people in the world. Mark Zuckerberg and a host of other Internet billionaires even awarded them a $3 million Breakthrough Prize. Zhang, however, was not impressed. “I thought, This is a very nice paper, but they haven’t shown that you can use it to do genome editing,” he says. Other researchers had already figured out many elements of the CRISPR system, he adds, saying, Doudna and Charpentier “had confirmed what I already knew from reading these earlier papers.”

To Zhang, actually getting the CRISPR system out of bacteria and working in human cells would be the real breakthrough. “You have to be able to edit the DNA inside of a human cell or mouse cell,” he argues. “It has to be a living cell.”

Lucky for Zhang, his lab was getting better at doing just that. By October 2012, he says, he was ready to submit his results to the journal Science. “Our paper is the paper that described how this will work,” he says, “and it provided the first demonstration of that.” Two months later, his paper was accepted. Zhang and his team celebrated with a bottle of champagne—Moët & Chandon. However, he soon learned that Church’s lab across town at Harvard had also gotten CRISPR to work in human cells, and that Church had also submitted a paper to Science—just three weeks after Zhang. The two papers were ultimately published together in the February 15, 2013, issue. By a slim three-week margin, Zhang became universally recognized as the first person on Earth to edit human cells with CRISPR-Cas9.

Ten months later, Zhang submitted a patent application for his gene-editing technique. He was shocked when the U.S. Patent and Trademark Office denied his request, explaining that Doudna and Charpentier’s 2012 paper had cracked the CRISPR code first. Wrong, Zhang and his attorneys fired back, noting that Doudna and Charpentier had not yet gotten CRISPR to work in human, animal, or plant cells.

After more than a year of back-and-forth with Zhang, the patent office finally issued him and the Broad Institute a patent for the CRISPR gene-editing technique in April 2014, leaving Doudna, Charpentier, and the University of California empty-handed. Zhang now held the exclusive right to use CRISPR in every living creature. That same month, though, the University of California decided to fight back, filing a 106-page “interference” appeal that challenged Zhang’s patent and launched a legal brawl that’s still raging today.

It didn’t take long for the dispute to start tearing apart the tight-knit community of CRISPR researchers. In 2013, Doudna had partnered with Zhang, Church, and other key Boston CRISPR scientists to cofound Editas. With $43 million in venture capital, it was supposed to be an unstoppable all-star endeavor. Two months after Zhang’s patent win, though, Doudna walked away from the startup—and took her intellectual property with her. She later licensed her knowledge of how to manipulate the CRISPR system to target and edit genes—based on her patent application—to a new CRISPR startup called Intellia Therapeutics, in Cambridge. A third company, CRISPR Therapeutics, which is based in Switzerland but has research offices in Cambridge, licensed Charpentier’s intellectual property based on the same patent application. In March, a panel of three patent judges took up the challenge to Zhang and the Broad Institute’s claim. Oral arguments in the case are scheduled for November of this year.

Much is at stake in this patent war: millions of dollars in future licensing fees, not to mention ego, scientific prizes, and glory. It’s no surprise, then, that both sides are playing hardball. Zhang and his legal team have taken a particularly strong stance, claiming Doudna’s discovery wasn’t a discovery at all and was already “obvious” to the scientific community. He also emphasized in his argument that his patent is expressly for editing humanlike cells, and all Doudna did was describe editing cells in bacteria. Still, when Zhang and Doudna talk about the patent dispute, each diplomatically balances competitiveness with a researcher’s interest in seeing disease cured and lives saved. “This is a very important technology,” Doudna says, and it “needs to be brought to market in ways that will benefit people ASAP.”

For geneticists like Zhang and Doudna—the Edison and Tesla of the DNA-editing world—scientific acclaim may be the biggest reward for the patent war’s winner. “Feng has been this close to two Nobel Prizes,” says Chad Cowan, a Harvard stem-cell biologist affiliated with CRISPR Therapeutics, Mass General, and the Broad Institute. “[With] optogenetics, he was just barely on the cusp, but really part of the team that pioneered that. And then CRISPR-Cas 9: He was working in parallel, on the same process, and probably months or weeks away from cracking it the same way Emmanuelle and Jennifer had.”

Cowan predicts that someone will almost certainly win the Nobel for CRISPR. He may be biased, since he’s with Charpentier’s company, but he thinks it’ll be Charpentier and Doudna. “And who knows,” he says, maybe “they’ll add somebody else.”

 


Erick Trickey Erick Trickey, Boston Magazine bmagdigital+etrickey@gmail.com