The Nobel Prize Committee in Stockholm announced today that it has awarded the 2020 Nobel Prize in Chemistry to Jennifer Doudna, Ph.D., and Emmanuelle Charpentier, Ph.D., the two women who pioneered the development of CRISPR technology as a “genetic scissors.”

Doudna, a structural biologist at the University of California Berkeley and the Howard Hughes Medical Institute (HHMI), was reportedly woken from a deep sleep in the middle of the night by a journalist.

A stunned Charpentier, shortly after the news broke, reflected on the historical significance of the award, the first time two women have shared the Nobel Prize.

“I think it’s very important for women to see a clear path,” she said. “I think the fact that Jennifer Doudna and I were awarded this prize today can provide a very strong message for young girls.”

Thelma and Louise

Doudna and Charpentier traveled in very different circles before their paths converged in early 2011, meeting for the first time at a microbiology conference in Puerto Rico. Doudna had enjoyed a highly successful scientific career, training with two Nobel laureates and joining the ranks of HHMI investigators in 1997. Charpentier, a French microbiologist, had kept a lower profile before her own breakthrough paper on one of the key components of CRISPR, called tracrRNA, was published in Nature in 2010.

In Puerto Rico, the two women agreed to forge a collaboration to study the mechanism of Cas9, the DNA-cutting nuclease at the heart of the one of the model CRISPR bacterial immune systems. Leading the charge was Martin Jinek, a Czech postdoctoral fellow in Doudna’s lab, and Krzysztof Chylinski, a Polish grad student in Charpentier’s group. The team made a key discovery, fusing the CRISPR (cr) RNA and tracrRNA into a “single-guide” RNA that could be programmed to target and cleave any sequence of DNA. Although genome editing was a powerful technology using other molecular systems such as zinc finger nucleases, CRISPR transformed scientists’ ability to rewrite the genetic code—in any organism.

Jinek reflected on the key steps in developing the sgRNA a CRISPR Journal interview published earlier this year:

“We then came up with the idea that if [crRNA and tracrRNA] are part of a duplex, then presumably the 3′ and the 5′ ends must not be too distant from each other. Then you can stitch them together with a loop. This was the kind of thinking one had to do in the field of structural biology of RNA… It was still a leap, but we were primed to have these ideas.”

The Doudna/Charpentier paper was published in Science in June 2012, with both women credited as corresponding authors. Leading commentators, including University of Utah biochemist Dana Carroll and microbiologist Rodolphe Barrangou (North Carolina State University), the chief editor of The CRISPR Journal, wrote contemporaneous commentaries discussing the implications of their breakthrough for genome editing in humans and other higher organisms.

“Only the future will tell whether this programmable molecular scalpel can outcompete ZFN and TALEN DNA scissors for precise genomic surgery,” Barrangou wrote in Nature Biotechnology. Carroll agreed. “Whether the CRISPR system will provide the next-next generation of targetable cleavage reagents remains to be seen, but it is clearly well worth a try,” he wrote in Molecular Therapy. “Stay tuned.”

But by this time, the Broad Institute’s Feng Zhang, Harvard Medical School geneticist George Church, had successfully performed CRISPR gene editing in human cells. Both of those studies were published in Science in January 2013. Several other groups, including Doudna and Jinek, demonstrated the same thing.

Despite the bitter ongoing patent dispute over the legal invention of CRISPR genome editing, Charpentier and Doudna’s discovery has already won numerous prestigious scientific awards, including the “Nobel Prizes” of Japan, Canada, Israel, and other countries. In 2018, they shared the Kavli Prize in nanoscience with Virginijus Siksnys, a Lithuanian biochemist. The French newspaper Le Monde dubbed the duo the “Thelma and Louise” of modern biology.

Nobel Speculation

Predictions over who would win the Nobel Prize for CRISPR have raged for several years. While some speculated that the award might come from the Physiology or Medicine committee, CRISPR-based therapeutics have only just entered the clinic. It will be many years before we see significant medical impact from the technology. That put the spotlight on Chemistry.

There was little doubt that, should a Nobel Prize for CRISPR be awarded in Chemistry, Doudna and Charpentier would claim two of the possible three slots. There has been much speculation about who a third recipient might be. Francisco Mojica, a Spanish microbiologist, first described the viral sequence homology of the “spacers” in the CRISPR arrays. Barrangou and Philippe Horvath led a landmark 2007 study that proved experimentally the anti-viral function of CRISPR.

Siksnys actually submitted a similar study to the Doudna/Charpentier work in early 2012, in which he coined the term “DNA surgery.” But his manuscript, which did not feature a single-guide RNA, was rejected by Cell. By the time it was published in PNAS, the story had moved on.

And of course there is Zhang, who published the first demonstration that CRISPR could edit the DNA of mammalian cells, in a collaboration with Rockefeller University microbiologist Luciano Marraffini, alongside a similar study from George Church’s group.

Church commented on the “credit” question in an interview last year with The CRISPR Journal.  Doudna and Charpentier “had not shown editing, and [Zhang’s paper] was side by side with ours… I did not want anybody to be left out… I felt that Martin Jinek had been left out of the story, and Prashant Mali and Luhan Yang and Le Cong.”

While debate over the Nobel selections might simmer in some quarters, Doudna’s former student (and co-author of A Crack in Creation), Samuel Sternberg, reflected on the award on Twitter.

“Nobels are also bittersweet, because [so] many more folks deserve the award than can receive it. Michael ‘Michi’ Hauer was the first to purify Cas9 in Jennifer’s lab, while working with Martin Jinek. He died last year, but would have been ecstatic to hear the news today.”