Few fields are as competitive as CRISPR gene editing. In fewer than six years, the precision DNA editing tool has appeared in over 9,000 scientific publications, spurred the formation of more than a dozen biotech companies, ignited a fierce patent dispute between its inventors, and stimulated much speculation over who will, and who won’t, one day receive the Nobel Prize for its creation.
So when two of CRISPR’s oft-cited inventors win a prestigious scientific award, and a third inventor doesn’t, people in the field talk.
On May 31, the Norwegian Academy of Science & Letters awarded its biennial Kavli Prize in Nanoscience to three of CRISPR’s pioneers “for the invention of CRISPR-Cas9, a precise nanotool for editing DNA, causing a revolution in biology, agriculture, and medicine.” Unsurprisingly, the winners included Emmanuelle Charpentier of the Max Planck Institute for Infection Biology, and Jennifer A. Doudna of the University of California, Berkeley. The duo was the first to publish the invention of the CRISPR gene editor together in June 2012 (Science 2012, DOI: 10.1126/science.1225829).
The third winner, Virginijus Siksnys of Vilnius University, an often forgotten CRISPR pioneer, independently elucidated CRISPR-Cas9’s potential for gene editing in a paper published in September 2012 (Proc. Natl. Acad. Sci. USA 2012, DOI: 10.1073/pnas.1208507109). All three Kavli winners will receive a combined $1 million and each will receive a gold medal.
Conspicuously absent from the awardees list is Feng Zhang, a young scientist from the Broad Institute of MIT and Harvard whose group also independently developed CRISPR gene editing and was the first to use the tool in mammalian cells in a paper published in January 2013 (Science 2013, DOI: 10.1126/science.1231143).
“CRISPR is an interesting case, prize-wise,” says Nathaniel Comfort, a history of medicine professor at Johns Hopkins University. “It involves two big, well-funded teams with large public-relations machinery—Team Doudna-Charpentier and Team Zhang—as well as several individual and far-flung researchers with little or none.” Those other researchers, including Siksnys, have won their own awards, but with considerably less fanfare compared with what Charpentier, Doudna, and Zhang have received.
“Emmanuelle Charpentier and Jennifer Doudna have been collecting prizes at an unprecedented rate,” says Dana Carroll, a biochemist at the University of Utah School of Medicine. The pair has shared more than a dozen awards, including the Breakthrough Prize in Life Sciences and the Warren Alpert Foundation Prize. “Siksnys has gotten less recognition, so I think it is appropriate that he should be acknowledged,” Carroll adds.
There is debate over who should receive the CRISPR fanfare because the publication timeline for the tool’s invention is complicated. Siksnys submitted a paper to PNAS in May 2012 reporting how Cas9, the molecular scissors of CRISPR, is guided to make specific cuts in DNA with the help of a complementary RNA strand. Charpentier and Doudna submitted a similar manuscript to Science in June that went a step further to engineer a guide RNA, which is essential for easily directing the CRISPR complex to almost any site in the genome. Their paper was reviewed, accepted, and published in just three weeks, appearing online on June 28, 2012. Siksnys’s paper didn’t appear online until September.
That twist of fate in timing, and Doudna’s and Charpentier’s extra feat of RNA engineering, thrusted the duo into the CRISPR spotlight. Doudna, in particular, has actively discussed the many ethical quandaries gene editing raises. In April, she became the second woman ever to receive the Gustavus John Esselen Award for Chemistry in the Public Interest, which is given by the ACS Northeastern Section. But even as Doudna continues to receive the most public recognition for CRISPR, Zhang may hold the strongest grip on CRISPR patents.
While a single CRISPR patent filed by Charpentier, Doudna, and colleagues is still pending, a large collection of Zhang’s CRISPR patents have already been approved. Both groups attempted to patent CRISPR gene editing applications in eukaryotes, which includes fungi, plants, animals, and humans. But at the time of filing the patents, only Zhang had demonstrated CRISPR gene editing was feasible in eukaryotes. Charpentier and Doudna had performed experiments only on DNA in a test tube and in bacteria, which are prokaryotes.
The ensuing patent dispute hinged on a technicality: Was making the jump from prokaryotes to eukaryotes nonobvious?
The patent court sided with Zhang, saying his application of CRISPR to eukaryotic cells constituted a unique invention separate from what Charpentier and Doudna were trying to patent. The latter group decided to appeal the decision, raising the dispute to the U.S. Court of Appeals for the Federal Circuit. A decision from the court is expected in the coming months.
If the court rules against Charpentier and Doudna, they could still try to get their patent application approved. But according to Jacob Sherkow, a law professor at New York Law School who has been following the case closely, the duo’s patent application could face two problems. “First, the patent application didn’t properly disclose how to work this technology in eukaryotes,” Sherkow says, which means any claims of using CRISPR in eukaryotes could be rejected by the patent examiner. “Second, it looks like someone else invented their invention earlier.” And that person is Siksnys.
Siksnys filed his CRISPR patent about six weeks before Charpentier and Doudna did, although it wasn’t public knowledge at the time. Now that Siksnys’s patent has been accepted, Charpentier’s and Doudna’s patent must be proven sufficiently different from Siksnys’s.
The patent tangle doesn’t appear to be preventing anyone from plowing ahead with CRISPR research or business development, however. Zhang is a cofounder of several CRISPR-based companies, including the start-ups Arbor Biotechnologies, Pairwise Plants, and Beam Therapeutics, all of which launched this year. Charpentier is a cofounder of CRISPR Therapeutics, which is expected to test an experimental treatment using CRISPR to treat sickle cell disease later this year. And Doudna recently cofounded a CRISPR-based diagnostics company called Mammoth Biosciences.
Siksnys has commercial ambitions too. He and his former student Giedrius Gasiunas were two cofounders of a Lithuanian start-up called CasZyme, which launched last year. It’s already formed partnerships with Corteva and New England Biolabs to discover, characterize, and commercialize new forms of CRISPR beyond the traditional CRISPR-Cas9.
The large number of characters in the CRISPR story “offers a particularly wide range of possible combinations for prizes, each with their justifications,” says Comfort, the Johns Hopkins medical historian. “It will be interesting to watch the major prizes in the coming years, to see upon which combination the consensus settles in the ultra-high-stakes campaign for credit for CRISPR.”