In early 2012, Emmanuelle Charpentier, a little-known French microbiologist who would soon meet worldwide fame, contacted her old friend Rodger Novak to tell him about her recent studies at Umeå University in Sweden of the mechanisms behind a novel bacterial immune system. “She said, ‘Hey, what do you think about CRISPR?’” recalls Novak, a biotech executive who more than a decade earlier had worked with Charpentier in academic labs studying antibiotic resistance. “I had no clue what she was talking about.”
It was only later that Novak learned that Charpentier, in collaboration with a prominent structural biologist, Jennifer Doudna of the University of California (UC), Berkeley, had transformed the CRISPR immune system into a tool that could edit genomes with great ease. As they and colleagues noted in what has become a landmark Science paper, published online 28 June 2012, this tool had “considerable potential.”
That November, Novak, who by then had become a vice president at Sanofi in Paris, and another old friend, Shaun Foy, a venture capitalist in Vancouver, Canada, discussed CRISPR’s commercial potential during a surfing trip to the challenging, frigid waters off the northern tip of Vancouver Island. Neither had ever surfed, but they both liked adventures. So Foy’s assessment, which came a month later after he had done what he calls his “diligencing,” wasn’t surprising. “He said I had to leave my job,” Novak says.
Novak, Foy, and Charpentier began speaking with others at the CRISPR research front about starting a company. “We were, as far as I know, the first ones to really think of that and really try to put something together,” says Charpentier, who is now at the Max Planck Institute for Infection Biology in Berlin. They set out to bring all the leading lights of CRISPR on board. It was a tiny research community then—in 2012 only 126 papers were published on CRISPR, compared with 2155 last year—and this simple vision seemed healthy for the field: practical and intellectually turbocharged. “We thought in the beginning it would be very important to bring everyone together,” Charpentier says.
After discussing the idea with Doudna, they floated the concept by two key CRISPR researchers in Cambridge, Massachusetts: George Church at Harvard University and his former postdoc Feng Zhang of the Broad Institute, who had just published their own widely noticed Science papers showing that the CRISPR system could guide its bacterial enzyme, Cas9, to precisely target and cut DNA in human cells. “One of the goals was to simplify the process of intellectual property,” Charpentier says.
But the attempt at unity collapsed—with a good deal of noise and dust. “I wish that it had worked out differently,” says Doudna, who also liked the concept of everyone working together. Over the next year and a half, as the science grew even more compelling and venture capital (VC) beckoned, the jockeying to start CRISPR companies became intense. The small community of researchers was rent apart by concerns about intellectual property, academic credit, Nobel Prize dreams, geography, media coverage, egos, personal profit, and loyalty. Adding to the divisive forces were the interests of the prestigious and powerful institutions that had a stake in the spoils—which in addition to UC, Broad, and Harvard included the Massachusetts Institute of Technology in Cambridge and the University of Vienna.
In the end, three companies formed to try to exploit CRISPR to create novel medicines, while Broad and two other companies licensed the technology to partners that hoped to engineer everything from improved crops and livestock to better animal models and industrial chemicals. A billion dollars poured into what might be called CRISPR Inc. from VC firms, pharmaceutical companies, and public stock offerings. Tens of millions of that money went to lawyers as the companies and the academic license holders faced each other down in a battle royale at the U.S. Patent and Trademark Office (USPTO). “It reminds me of reading about really unhappy rich people,” says Church of the epic patent fight. “They have such a big blank check that they just make each other miserable.”
As the players anxiously await a ruling from USPTO, Science took a close look at how the enterprise fractured, drawing on documents from the patent litigation, Securities and Exchange Commission filings, licensing agreements, and interviews with the central figures. Church, who describes himself as “an inclusive guy” and made his own attempt to bring the top researchers together under one roof, believes that in the long run the splintering of the field will probably work out fine for the companies, their investors, the principal researchers, and the public. “It’s good enough,” says Church, who has equity in two CRISPR companies that focus on human therapeutics. “But it’s not all for the good.”
CRISPR FIRST BECAME A BUSINESS with yogurt.
The dairy industry uses the bacterium Streptococcus thermophilus to convert lactose into lactic acid, which gels milk. Viruses called bacteriophages can attack S. thermophilus, spoiling the yogurt culture. In 2007, Rodolphe Barrangou and Philippe Horvath were working at Danisco, one of the world’s leading makers of yogurt cultures, when they found that the S. thermophilus genome contains odd chunks of repeated DNA sequences—so-called clustered regularly interspaced short palindromic repeats (CRISPR), which Spain’s Francisco Mojica had first described in 1993 in the genome of the salt-loving microbe Haloferax mediterranei. The Danisco team found that the CRISPR sequences match the phage DNA, enabling S. thermophilus to recognize and fight off infections.
DuPont, which acquired Danisco in 2011, began using the insights to create bacteriophage-resistant S. thermophilus for yogurt and cheese production. Today, “whether you’ve had yogurt in Tel Aviv or nachos in California, you’ve eaten a CRISPR-enhanced dairy product,” says Barrangou, who is now a food scientist at North Carolina State University in Raleigh.
Yet the idea that CRISPR could serve as a general-purpose genome-editing tool did not surface until a 19 December 2008 Science paper by Erik Sontheimer and Luciano Marraffini at Northwestern University in Evanston, Illinois. Sontheimer and his postdoc Marraffini were the first to show just how CRISPR protected bacteria: by identifying and crippling invaders’ DNA. “From a practical standpoint, the ability to direct the specific, addressable destruction of DNA … could have considerable functional utility, especially if the system can function outside of its native bacterial or archaeal context,” they wrote.
USPTO, however, rejected their patent application. “The vision and idea were out there, but we hadn’t reduced it to practice,” says Sontheimer, who is now at the University of Massachusetts Medical School in Worcester. “When we filed our patent in 2008 there were a million mechanistic questions.”
In 2011, Doudna co-started Caribou Biosciences as what she calls “a research tool company” to exploit the possibility that CRISPR could be used to simplify detection of viral infections like HIV. But the real flowering of CRISPR Inc. didn’t begin until the next 2 years, when this obscure bacterial immune system showed its power as the versatile tool that Sontheimer and Marraffin had only imagined. First came Doudna and Charpentier’s paper describing a CRISPRCas9 system that could cut DNA in a test tube. Six months later, in January 2013, Zhang (working with Marraffini), Church, Doudna, and a fourth group separately reported that they could export CRISPR-Cas9 to human cells, which meant that it might be put to work in medical treatments…….
