The Battle Over Genome Editing Gets Science All Wrong
Nobel prize speculation, gossip, and betting pools kick off every fall around the time Thomson Reuters releases its predictions for science’s most prestigious prize. This year, one prediction was unusual: a genome-editing tool so hyped that it even got on the cover of WIRED.
(No, seriously, how often does molecular biology get to occupy the same space as Star Wars or Rashida Jones?)
The tool, Crispr/Cas9, is essentially a pair of molecular scissors for editing DNA, so precise and easy to use that it has taken biology by storm. Hundreds if not thousands of labs now use Crispr/Cas9 to do everything from making super-muscled pigs to snipping HIV genes out of infected cells to creating transgenic monkeys for neuroscience research. But the Nobel prediction stands out for two reasons: First, the highly-cited paper describing Crispr/Cas9 came out a mere three years ago, a blip in the timescale of science. Second, the technique is currently at the heart of a bitter patent fight.
Thomson Reuters bases its predictions on how often key papers get cited by other scientists. Here, the paper in question has as its authors Jennifer Doudna, a molecular biologist at UC Berkeley, and Emmanuelle Charpentier, a microbiologist now at the Max Planck Institute for Infection Biology. Missing is Feng Zhang (no relation to this writer), a molecular biologist at the Broad Institute and MIT, who actually owns the patents for CRISPR/Cas9 and says that he came up with the idea independently. So let’s say Thomson Reuters gets it right. Could the patent for a discovery go to one scientist, and the Nobel prize for the discovery to someone else?
The two groups—or their patent lawyers, really—are in fact fighting over credit for CRISPR/Cas9. At stake are millions of dollars already poured into rival companies that have licensed patents from the two different groups.
But putting aside all the lawyers and all the money for a moment, obsessing over finding the one true origin of Crispr/Cas9 gets science all wrong. Casting the narrative as Doudna versus Zhang or Berkeley versus MIT is a misapprehension of history, creativity, and innovation. Discovery comes not from a singular stroke of genius, but an incremental body of research. “I’m not a great believer in the flash-of-genius theory. If you are a historian—” says Mario Biagioli, who is in fact a historian of science at UC San Diego—“you quickly will realize exactly how many times there are independent discoveries of the same thing.” The dispute over credit for CRISPR/Cas9 is not the result of exceptional coincidence and disagreement. In fact, it illuminates how science always works.
The Other Crispr Scientist
The story of how Doudna, Charpentier, and Zhang came to discover Crispr/Cas9 has been told many times, including by WIRED. So I want to tell a different story—a largely forgotten one, about Crispr’s early days.
Virginijus Siksnys is a molecular biologist at Vilnius University in Lithuania. He got interested in Crispr in 2007, when scientists working with yogurt bacteria first realized that odd repeats in their DNA—the “clustered regularly interspaced short palindromic repeats” that give Crispr its name—are in fact part of an ancient microbial immune system that fights viruses. The bits of DNA between the repeats were viral sequences, essentially mug shots for for the pathogens. The bacteria also had Crispr-associated proteins (the “Cas” in “Cas9”) that seemed to use these mug shots to cut up the genetic material of invading viruses.
“In my lab we didn’t know how to make cheese or yogurt, but we know how to work with E. coli,” says Siksnys. So his lab took the Crispr and Cas sequences from yogurt bacteria and stuck them inside E. coli cells, which made those bacteria suddenly immune to some viruses. In E. coli, the researchers could delete the Cas genes one by one, and by 2012, Siksnys had honed in on one in particular, which coded for Cas9, solely responsible for snipping DNA. In May, they submitted a paper detailing exactly how Cas9 cuts DNA to the Proceedings of the National Academy of Sciences. Peer reviewers came back with questions and that back and forth took a few months—typical of peer review.
Here is where the more famous narrative intersects. That June, a month after Siksnys’ lab submitted their paper, Doudna and Charpentier’s paper came out in Science—with many of the same findings as Siksnys’. (The key difference is that Doudna and Charpentier’s paper shows that the two pieces of RNA that Cas9 needs to work can be fused into one chimeric segment.)
Science’s editors, who obviously saw something big on their hands, fast-tracked the paper’s review, and published it within a month of submission. The paper made a huge splash.
“Of course, we were disappointed,” says Siksnys. His paper came out in PNAS in September to less fanfare. By then, Crispr/Cas9 was off to the races. Zhang and George Church of Harvard published papers in February of 2013 showing that Crispr/Cas9 could alter human cells in a dish; their work also further refined Cas9’s DNA-editing abilities.
Then the US patent office awarded Zhang the patent, even though Doudna had filed first, sparking a fight between the University of California and the Broad and MIT. The US Patent and Trademark Office is trying to work it all out. (Doudna and Zhang declined to comment for this story.)
So while everyone is arguing about whether Doudna and Charpentier or Zhang deserve credit for discovering Crispr, popular accounts of the discovery—WIRED’s included—have left out Siksnys’ contribution. His paper also has received a fraction of the citations that Doudna’s has. “Yes, I think of course my lab deserves credit because what we discovered was done independently in two labs,” Siksnys says. “It’s a very competitive field,” he adds diplomatically. “It’s part of the game.”
Part of the Game
The eminent sociologist Robert Merton, who made a career out of studying scientists, writes about how every field of research builds upon an “accumulated cultural base.” (Real catchy, I know.) What he means is that discoveries don’t drop out of the air—they’re products of their time.
Siksnys, Doudna, Charpentier, and Zhang all cracked Crispr/Cas9 around the same time because they all built on the same research from yet other scientists who figured what Crispr actually is. The 2007 paper kicked off a race. “People were working on the Crispr system,” says Dana Carroll, a gene-editing expert at the University of Utah who was paid to write a technical analysis in support of Doudna’s patent. “They were kind of inching toward what the Doudna and Charpentier group finally demonstrated.” Doudna and Charpentier published first, by a hair.
Dan Voytas, a gene-editing expert at the University of Minnesota, credits yet other researchers, like Carroll, who worked on earlier gene-editing systems that made the insight into Cas9 as a tool even possible. Figuring out that a DNA-cutting protein like Cas9 could be used to edit DNA is actually not a no-brainer. (You can only do so much with scissors and no glue.) Carroll and other researchers, working on another gene-editing technique called zinc-finger nucleases, found that when you cut DNA, one of two things can happen: The cell will 1) try to repair the cut by adding gibberish letters of DNA, rendering target gene useless or 2) insert a snippet of DNA chosen by the researcher. That second one is way better. Without this work, no one would have been able to tell how useful Crispr/Cas9 could be.
By the early 2010s, the two lines of inquiry into Crispr and into gene-editing systems met. It was CRISPR/Cas9’s time. Scientists had their accumulated cultural base. (Yeah, no, still not catchy.)
None of this history diminishes the hard work or intellectual acuity of individual scientists. Mentioning Siksnys’ research does not diminish Doudna and Charpentier’s. Mentioning Douda and Charpentier’s research doesn’t diminish Zhang’s.
History is full of parallel discoveries: Isaac Newton and Gottfried Leibniz independently discovered calculus in the late 17th century and then spent years fighting over who got there first. Charles Darwin and Alfred Russel Wallace both came up with the theory of evolution through natural selection, though these two had a more amiable relationship. Back in 1922, the sociologists William Ogburn and Dorothy Thomas catalogued 150 examples of independent discovery and invention. Merton even went so far as to say single discoveries are the real oddities. Scientists naturally flock to the interesting scientific problems of their time, and again naturally, they use the tools of their time to solve them. No wonder they often come up with the same solutions.
The problem is, though, is that Nobel prizes go to a maximum of three people, and patents only to one group of inventors. Journalists want one good story rather than a tangle of characters. If you’ve found keeping track of all the names in this story difficult, well, yes.
Ultimately the messy process of science gets reduced to a single moment. “A discovery is not always an absolute discrete moment, but something that has to be negotiated,” says Nathaniel Comfort, a historian of medicine and science at Johns Hopkins University. People come to the table with different amounts of power. “That has a lot to do with ego, storytelling ability, and clout within the field. Who are the people who have the most power and get listened to?” says Comfort.
When asked why Doudna’s paper has so eclipsed Siksnys’, Carroll noted it was in fact published first. But also, “it may have something to do with the fact that Jennifer Doudna was very accomplished and known in the molecular biology community before this Crispr breakthrough.” Doudna may not be a household name among non-scientists, but she was already a big shot for earlier groundbreaking work on RNA. Zhang, on the other hand, has a reputation as a wunderkind, having worked on optogenetics (another discovery tipped to win a Nobel prize someday), an earlier genome-editing tool called TALENs, and now Crispr/Cas9—all before the age of 35.
Both researchers also have powerful institutional PR machines behind them. The Broad Institute has built an educational site with a timeline and a press release for a recent Crispr paper that other researchers have actually been criticized for minimizing Doudna’s work.
— Michael Eisen (@mbeisen) September 25, 2015
Passive-aggressive, aggrandizing moves like these are hardly unusual. In Slate, for example, Laura Helmuth wrote about the National Institutes of Health’s curious decision to celebrate the anniversary of the sequencing of the human genome two years after the more widely agreed-upon date—all to play up the NIH over J. Craig Venter’s Celera. And just a couple weeks ago, Nature reported on two rival groups fighting over the possible discovery of a protein that lets animals sense magnetic fields. Why such a big deal? Because it might win a Nobel prize, one of the researchers told the journal.
With few exceptions, though, most of the scientists I’ve ever spoken to have been happy to credit their predecessors and collaborators. Scientists are well aware that they, as Newton put it, stand on the shoulders of giants. That’s why journal articles cite previous journal articles. But when the science meets patent law or the popular press or Nobel prizes, those nuances get lost.
Conventional wisdom says that it’s probably way too early for Crispr/Cas9 to win a Nobel prize next week. Its true potential—in curing human diseases—is still just potential. And last week, Zhang’s lab reported finding another Crispr system that uses a different protein to cut DNA, which not only gives his lab its own free-and-clear discovery but, more importantly, suggests researchers might be able to find a whole library of editing proteins. As one scientist put it, the discoveries to date might just be “the tip of the iceberg.”
The story of Crispr is only just beginning, but the scramble to write it is already well underway.
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