The Embarrassing, Destructive Fight over Biotech's Big Breakthrough
A defining moment in modern biology occurred on July 24, 1978, when biotechnology pioneer Robert Swanson, who had recently co-founded Genentech, brought two young scientists to dinner with Thomas Perkins, the legendary venture capitalist. As they stood outside Perkins’s magnificent mansion in Marin County, with its swimming pool and garden and a view of the Golden Gate Bridge, Swanson turned to his two young colleagues and said, “This is what we’re all working for.”
That scene came to mind as I sorted through the tawdry verbal wreckage on social media and in print of the “debate” over CRISPR, the revolutionary new gene-editing technology. The current brouhaha, triggered by Eric Lander’s now-infamous essay in Cell called “The Heroes of CRISPR,” is the most entertaining food fight in science in years.
The stakes are exceedingly high. CRISPR is the most important new technology to hit biology since recombinant DNA, which launched Genentech, made Swanson, along with his colleagues and investors, rich and brought molecular biology, long the province of academia, into the realm of celebrity and big money. In this context, the Cell essay has huge patent and prize implications. Lander has been accused of writing an incomplete and inaccurate history of the CRISPR story, burnishing the patent claims of the Broad Institute in Cambridge, Mass., (he is its director) and minimizing the contributions of rival scientists. A blogger has referred to him as “an evil genius at the height of his craft.” And George Church, a colleague at the Broad Institute, likens Lander to a figure out of a Greek tragedy. “The only person that could hurt him was himself,” he says. “He was invulnerable to anybody else’s sword.” And you thought scientists couldn’t talk smack.
Spectators, scientific and otherwise, have followed this bitter dispute with fascination but the fight is destructive--and far from over. In waging a nasty public battle over CRISPR, the protagonists have given science a black eye for the reason Swanson suggested on that long-ago night in Marin County: money and glory. In waging a nasty public fight over CRISPR, they have already attracted the scrutiny of the mainstream press (The Washington Post and the Boston Globe Media’s STAT, to name two avid voyeurs), the scientific press and, oh boy, the Internet. The trash talking has undermined the public image of science, raised unflattering questions about the motives of scientists and institutions and, less obviously, fueled doubts about the judgment of leading scientific journals, which act as unofficial auditors of the billions of taxpayer dollars spent on biological research. The spat is like an escalating and increasingly ugly domestic dispute: no one wants outsiders to get involved but the screaming has gotten so loud that somebody has to call the cops. The fight over CRISPR is getting to that point. Woe be it to science if the politicians step in and use the fight as an excuse to rethink funding or the rules of technology transfer.
The scientific story has deep roots. Scientists glimpsed the first hint of CRISPR biology in the 1980s and primitive forms of gene-editing arose in the 1990s. But a crucial leap occurred in 2012 when a group led by Jennifer Doudna of the University of California, Berkeley, and Emmanuelle Charpentier, now at the Max Planck Institute for Infection Biology in Berlin, demonstrated the possibility of simple CRISPR-based gene-editing to a broad audience of scientists with a paper in Science. The University of California and the University of Vienna filed for a patent, listing Doudna, Charpentier and other individuals. But the U.S. Patent and Trademark Office issued a patent in 2014 to Feng Zhang of the Broad Institute, which filed its application after Berkeley but requested expedited consideration. The University of California has challenged the validity of all the Broad patents (now numbering about a dozen) and the ensuing “interference” proceedings may allow another year of trash talking by scientists and bloggers alike. Meanwhile the protagonists—and their institutional proxies—continue to jockey for priority, prizes and reputation.
Against this backdrop, Lander’s piece came as a shock. Lander is director of the Broad Institute and therefore someone with a very big dog in the patent fight. Maybe by calling it a “Perspective” the editors of Cell were signaling Lander’s obvious conflict of interest; nothing else in the article did.
Let me note, first, that “The Heroes of CRISPR” is beautifully written. In addition to being a fabulous scientist and truly visionary thinker, Lander is a terrific communicator. His history reads at times like high-end magazine journalism (the story begins in Spain’s Costa Blanca, “where the beautiful coast and vast salt marshes have for centuries attracted vacationers, flamingoes and commercial salt producers”) with almost novelistic detail (Zhang, born in China and reared in Des Moines, has his eureka moment while “holed up” in a Miami hotel)—not your average journal prose. Lander’s account of the early work on CRISPR, often overlooked, is thorough, accurate and generous, according to people who know the history well. And it’s written as a feel-good story with an inspirational take-home message: People who work off the beaten track, in both the geographic and biological sense, often make dramatic contributions to the “remarkable ecosystem underlying scientific discovery,” he notes. Scientific breakthroughs are “ensemble acts” that unfold over many years. “It’s a wonderful lesson for the general public,” Lander concludes, “as well as for a young person contemplating a life in science.”
Beautifully put. So why did the Twitterverse go radioactive on Lander within hours of the article’s publication on January 14?
As I often suggest to students in my science journalism classes, just because a story is beautifully written doesn’t mean that it is true—in whole or in part. Judging from the firestorm of criticism, “The Heroes of CRISPR” falls short on a number of issues, beginning with this awkward money-tinged paradox: If the CRISPR story (and science in general) is such a beautiful ensemble activity, why is there only one name on the Broad Institute’s patent? Well, patents have to do with money, and money turns a lot of beautiful scientific stories into ugly legal narratives.
Case in point: in 1979, a year after Bob Swanson’s pep talk to his Genentech biologists, a biologist then at Columbia University named Michael Wigler published a very clever method (called “co-transformation”) for smuggling genes into eukaryotic cells; the university filed a patent application in 1980, with Wigler and two colleagues as inventors, and received the first of several patents in 1983. Like CRISPR, the technique may sound esoteric but biologists (and companies) quickly recognized its value, and Columbia ultimately reaped nearly $800 million from those patents. (Other, unofficial estimates run between $1 billion and $1.5 billion.) Columbia became so enamored of the revenue stream that it resorted to several controversial tactics, including having a U.S. senator try to extend the patent by slipping language into an agricultural bill. These maneuvers prompted an uproar and were later characterized, by historians of genomics Robert Cook-Deegan and Alessandra Colaianni, both then at Duke University, as “behavior unbecoming a nonprofit academic institution.”
Wigler, who now runs a lab at Cold Spring Harbor Laboratory, says of the Columbia patent: “Of course it’s had an impact on institutions, because institutions are desperate for money.” That’s why the University of California and the Broad Institute (a joint venture of Harvard University and Massachusetts Institute of Technology) will fight fiercely—“red in tooth and claw,” you might say—to claim intellectual property on CRISPR.
Many readers (including me) interpreted Lander’s elegant history of CRISPR as a calculated attempt to elevate the intellectual contribution of Zhang (the Broad Institute scientist who is recognized, for the moment, by the patent office as the lone “inventor” of CRISPR) as it minimizes the contributions of Doudna and Charpentier. (Zhang’s discovery narrative is long, detailed and colorful; Doudna’s appearance comes in the middle of a paragraph, and her work doesn’t get nearly the same star treatment.) In other words, this beautifully crafted history can also be read as a patent brief in disguise. (A blog by science historian Nathaniel Comfort shrewdly deconstructs the rhetoric used by Lander to advance Broad’s interests. Inexplicably, Cell didn’t even mention Lander’s flagrant conflict of interest (an instance of editorial neglect to which we’ll return later).
Both Doudna and Charpentier quickly posted frostily brief comments to PubMed Commons; Doudna claimed the description of her lab’s work was “factually incorrect,” and Charpentier characterized her part of the story as “incomplete and inaccurate.” Church, whose Harvard lab published on the utility of CRISPR gene-editing in mammalian cells at the same time as Zhang’s, disputed Lander’s history as well in press accounts. When I spoke with Church about a week after the Cell article came out, he was not shy about itemizing. “Normally I’m not so nitpicky about all these errors,” he said. “But as soon as I saw that they [Lander and Cell] were not giving the young people, the people who actually did the work, and Jennifer and Emmanuelle, adequate credit, I just said, ‘No, I have to correct what I know to be false.’” (Lander was “delighted” to append Church’s clarifications to the Cell article). Church acknowledged that the essay was “exquisitely crafted,” but crafted, in his view, with an ulterior motive. “It was like, ‘I’m going to prove my point of view,’” he said. But according to Church, Lander may have achieved the exact opposite effect. “I think Jennifer and Emmanuelle deserve a lot of credit,” he said. “And the more you try to take it from them, the more people want to give it to them.”
In truth, there are a lot of moving parts and proxies in this messy battle. The hostilities involve institutions (M.I.T. and Harvard versus University of California), gender (Doudna, Charpentier, Zhang), geography (east versus west coast) and what you might call über-institutions (the Broad Institute, which has become an empire of genomic research under Lander’s direction, especially after his leading role in the Human Genome Project, versus the Howard Hughes Medical Institute, whose president, Robert Tjian, is based at Berkeley and has co-authored at least one CRISPR paper with Doudna, also an HHMI investigator). Probably because of this combustible mix of interests, the debate over the Cellarticle has become especially nasty; whatever used to be the line of decorum in scientific debate, it was breached within 24 hours after theCell article appeared.
And a lot of the invective has been surprisingly personal. Michael Eisen, an HHMI researcher at Berkeley, has been particularly outspoken in his blog. The Cell essay was “an elaborate lie,” Eisen wrote on January 25, and his attack didn’t stop there.
Lander is in Antarctica and unavailable for comment, according to a Broad Institute spokesperson. But in an e-mail to the Broad staff on January 28 he reiterated his pride in writing the essay and added: "Needless to say, 'Perspective' articles are personal opinions. Not everyone will fully agree with anyone else's point of view. In the end, we come to understand science only by integrating a diverse range of thoughtfully expressed perspectives. And, when scientific discovery is also the subject of patent disputes (as is the case with U.C. Berkeley and Broad–M.I.T.), intellectual disagreements can, as here, give rise to vigorous online discussion." As for the conflict-of-interest issue, Broad spokesperson Lee McGuire noted that Lander had previously "disclosed the fact that he has no personal financial interest and that the institute he represents does license CRISPR technologies."
The dirty truth is that long before Lander’s Cell article the scientific community has been watching this food fight—for patent dollars, for credit, for prizes—with increasing dismay. Both Zhang and Doudna have been subtly lobbying for recognition in what one scientist characterized to me, dismissively, as “their little Nobel talks—they don’t give seminars anymore.” Doudna, Charpentier and Zhang are all outstanding researchers and very likable people but they appear caught up in the vortex of scientific politics and recognition spin. If it were your work and someone was trying to devalue it, you’d defend it to the hilt, too. But the ongoing drama is not a good look for science, and some of the “heroes of CRISPR” are wearing out their welcome on the public stage. “This is not David versus Goliath,” one disgusted scientist told me recently. “This is Goliath against Goliath. These two camps deserve each other, and they can bully each other into oblivion.”
Why would such a shrewd and strategic thinker like Lander tempt such a public backlash by writing such a cleverly slanted history? Perhaps his ultimate audience was not Cell’s readers nor even the scientific community at large but rather a very small (and select) group of readers in Alexandria, Va. A gifted writer, Lander set out to produce a seemingly neutral and magnanimous history of CRISPR that even an examiner at the U.S. Patent and Trade Office could understand. (If this sounds condescending, consider how Wigler summarizes 35-plus years of dealing with the patent system: “My general experience with the patent office is that they don’t get it. They don’t understand this stuff.”)
The Lander article has inflicted some surprising collateral damage, notably to scientific publishing itself. Cell’s decision to publish the article, despite the Broad’s clear financial interest in the patent dispute, invited withering criticism. (The journal stated that it "regularly" evaluates its policies, and "will include" in that process the role of institutional conflicts of interest.) And if CRISPR is “the century’s biggest biotech innovation,” as a blogger for The Washington Postrecently noted, what does it say about the quality of scientific journals that in at least 10 instances “seminal papers,” according to Lander’s Cell article, were rejected by journals like Nature,Proceedings of the National Academy of Sciencesand even Cell itself? In many cases, editors at these journals did not even send out the articles for peer review. Virtually all this research is paid for at least in part by public money, which raises an inconvenient question: Is the public interest served by journals that don’t even recognize scientific excellence? Does Cell even give a hoot about public perception? Here’s what one prominent scientist told me about Cell’s handling of the entire episode: “All they care about is how many times the article is cited in their citation index.” That and the traffic on Twitter.
That may hint at why the CRISPR dispute is so different, and so dangerous to the scientific community. Trash talking has been a part of science for centuries; Newton’s seemingly magnanimous remark that he stood “on the shoulders of giants” was, to the contrary, likely understood by his contemporaries to be a disparaging reference to the short stature of his main rival, Robert Hooke. But invective today gets amplified and disseminated so rapidly that it assumes a public life of its own, and scientific spats become a reality show complete with egos, self-promotion, greed and Machiavellian stratagems dissected in blogs, on social media and on bulletin boards.
And then there’s the influence of money. Since the summer of 1978 biotechnology has bestowed untold riches on companies, institutions and individual biologists. It has produced thrilling science and some wonderful (albeit pricey) new medicines. But it has also slowly eroded boundaries between appropriate and inappropriate behavior. Scientific narratives used to be cast in the past tense, about what had been accomplished; now the storytelling is in the future tense to raise venture capital (or, in the case of ‘Heroes,” in what might be called the past imperfect to advance a patent claim). Hype used to be frowned on; now it is part of every business plan. Since at least the 1990s biotech companies have tried to influence university research, and it is a commonplace that the pharmaceutical industry dictates the terms of much academic clinical research. Students, already demoralized by scarce funding and no jobs, fret over whether basic research (of the sort that produced CRISPR in the first place) will be as esteemed as “patentable” work—and if their names will even be included on the patent. And the red flags that used to signal conflicts of interest are so frayed that you can essentially see right through them. It’s not that Cell should have had a stricter policy about conflicts of interest, it’s that a protagonist in the patent dispute probably shouldn’t have attempted to write a history of CRISPR in the first place. After the Lander article was published Cell posted a statement on its Web site saying Lander had indeed communicated that his institutional affiliations—Broad, M.I.T. and Harvard—had patents and patent applications related to CRISPR but that the journal only considers "personal" conflicts of interest.
There is currently a lull in the CRISPR hostilities; no one has flamed anyone, by my count, in the last 72 hours. But that probably won’t last long. The patent interference, in which University of California lawyers will probably claim that its scientists invented CRISPR gene-editing and also applied for a patent before Broad, will be hotly contested. Maybe this little pause is an opportunity for a reset—a chance for the scientific community to acknowledge that the CRISPR system, as some have quietly suggested all along, was actually “invented” by bacteria eons ago as an ingenious immune response to viral infection, and that its rediscovery was accomplished by so many heroic (if you will) hands and with so much public coin that the technology ultimately belongs in the public commons and should not be patented and…
…Sorry, I got a little carried away there. Yes, it would be nice if the transformative power of CRISPR remained in the public domain; maybe we could even invent a new prize—the Rashomon Prize!—that recognizes all the key players, no matter how contradictory or self-serving their stories. But in the current ecosystem of biology, where institutions are indeed desperate for money and the rules of the game create winner-take-all slugfests, that is very unlikely to happen.