Credit for CRISPR: A Conversation with George Church

The media frenzy over the gene-editing technique highlights shortcomings in how journalists and award committees portray contributions to scientific discoveries.

By | December 29, 2015

George Church in 2010WIKIMEDIA, STEVE JURVETSONJennifer Doudna, Emmanuelle Charpentier, and Feng Zhang are widely cited as the primary developers of CRISPR/Cas9 technology. These researchers were undoubtedly key to the development of the bacterial immune defense system into a powerful and accessible gene-editing tool, but by assigning credit to just three individuals, most news reports overlook the contributions of countless other scientists, including George Church, who alerted The Scientist to this issue after reading an article on December’s Human Gene Editing Summit.

In the article, my colleague Jef Akst highlighted Doudna, Charpentier, and Zhang as the three seminal figures in the development of CRISPR/Cas9 technology: “The attendees are a veritable who’s who of genome editing: Jennifer Doudna of the University of California, Berkeley, Emmanuelle Charpentier of Max Planck Institute for Infection Biology, and Feng Zhang of the Broad Institute of MIT and Harvard—the three discoverers of the CRISPR-Cas9 system’s utility in gene editing—plus dozens of other big names in genome science,” Akst wrote. In assigning the lion’s share of credit for CRISPR/Cas9 gene editing to Doudna, Charpentier, and Zhang, Akst echoed countless articles on the technology’s origin story.

“I’m trying not to complain,” Church told me when we chatted a few days later. “I’m just making what I thought was a little technical correction, which was the particular way she phrased it.” His point? He and many other scientists also contributed to developing the “CRISPR-Cas9 system’s utility in gene editing.”

If you’ve read anything about CRISPR, you’re likely familiar with the following: in a 2012 Science paper, Doudna, Charpentier, and their colleagues published the first account of programming the CRISPR/Cas9 system to precisely cut naked plasmid and double-stranded DNA. Zhang and his colleagues applied this precision-cutting approach to mouse and human cells in vitro, publishing their results in a February 2013 issue of Science.

But, as is the case whenever intensive scientific inquiry in involved, the story was not nearly so simple. Although it’s not often included with the aforementioned studies, Church’s team published a similar study—using CRISPR/Cas9 to edit genes in human stem cells—in the same issue of Science as Zhang and his colleagues.

Church emphasized that Doudna and Charpentier were major players in elevating CRISPR/Cas9, a naturally occurring form of immune defense employed by bacteria to fight off invading viruses, from a biological curiosity to a potentially transformative gene-editing tool. “They were definitely pioneers in studying this particular enzyme system,” he said. But he contends that their specific contributions don’t constitute the whole story of the technology’s development. “The spark that [Doudna] had was that CRISPR would be a programmable cutting device,” Church said. “But getting it to do precise editing, via homologous recombination, was a whole other thing.”

The CRISPR/Cas system is a naturally occurring form of immune defense employed by bacteria to fight off invading viruses. A small constellation of researchers aided in describing, isolating, and studying CRISPR decades before it was ever imagined as a gene-editing tool.

In 1987, Yoshizumi Ishino and his colleagues at Osaka University in Japan published the sequence of a peculiar short repeat, called iap, in the DNA of E. coli . Eight years later, Francisco Mojica from the University of Alicante in Spain and his colleagues characterized what would become known as a CRISPR locus; The researchers later realized that what they and others had considered disparate repeat sequences actually shared common features.

Mojica and his colleague Ruud Jansen coined the term CRISPR (for clustered regularly-interspaced short palindromic repeats) in correspondence with each other in the late 90s and early 2000s, and Jansen used it in print for the first time in 2002. A steady trickle of research on the prokaryotic immune module followed, with industry scientists such as Philippe Horvath and Rodolphe Barrangou from dairy manufacturer Danisco joining academic researchers—among them, Luciano Marraffini at Rockefeller University, John Van der Oost at Wageningen University in the Netherlands, Sylvain Moineau of Canada’s Laval University, Virginijus Siksnys at Vilnius University in Lithuania, and Eugene Koonin of the National Center for Biotechnology Information—pursuing a more robust understanding of how CRISPR worked in nature. This early work on CRISPR was “kind of a community effort,” said Church.

Zhang agreed. “This is a remarkable scientific story in its own right, and the work on genome editing . . . was only possible because of a strong, global foundation of basic research into the biology of CRISPR,” he wrote in an email to The Scientist. “Many researchers contributed to the discovery and understanding of CRISPR,” he added. “Any discussion of the development of CRISPR into the genome-editing tool it is today would be incomplete without recognizing the critical contributions of each of these individuals and their teams.”

Now that the technology is being applied, its origin story has been oversimplified in both published accounts and by award organizations. “It’s a litany now,” Church said. “It’s like a hymn.”

And of all the researchers who might deserve more credit for developing CRISPR, Church contends that he’s at the top of the list. “There were definitely at least two teams [Doudna’s and Charpentier’s] involved in getting cutting to work,” Church continued, “and then there were two teams [Zhang’s and mine] that got it to work in humans with homologous recombination. So you could say two and two. But to oversimplify that back down to three, is like consciously omitting one.”

Why that happened isn’t readily apparent, said Doudna. “Looking at peer-reviewed publications, George Church published a paper at the same time in the same issue of Science magazine as Feng Zhang on using CRISPR technology in human cells,” she told The Scientist. “It’s very clear what’s in the scientific record.”

That CRISPR/Cas9 gene-editing was a larger collaborative effort that extends beyond Doudna, Charpentier, and Zhang is an issue that others have spoken and written about. An economic manifestation of the debate, in the form of a patent dispute, has even sprung up within the oft-cited CRISPR trinity. Then there are the prizes. In 2014, Doudna and Charpentier were awarded a $3 million Breakthrough Prize. And last year Thomson Reuters predicted a Nobel Prize in Chemistry for the duo. (The 2015 honors went to a trio of DNA repair researchers instead.)

Meanwhile, the media continues to perpetuate the condensed CRISPR origin story when mentioning the technology’s evolution in the space of a sentence or two. Part of that oversimplification is rooted in the fact that most modern life-science researchers aren’t working to uncover broad biological truths. These days the major discoveries lie waiting in the details, meaning that any one lab is unlikely to shed all the necessary light on a complex phenomenon—much less on how to adopt that phenomenon for human purposes—in isolation. That reality does little to allay what is probably a fundamental human urge to pin a few names and faces on major breakthroughs.

But how do we fix a problem of public perception that stems from the very nature of scientific discovery in the modern age? Doudna had a suggestion. “I think it’s great that journalists look into this and explain the process of science,” she said. “Things don’t happen overnight; they happen through a process of investigation. And very typically there are multiple laboratories that are working in an area, and it’s almost universally true.”

Correction (January 2): The orignial version of this article gave an incorrect primary affiliation for Eugene Koonin. He is at the National Center for Biotechnology Information and the National Library of Medicine. The mistake has been corrected, and The Scientist regrets the error.

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Avatar of: ElDuderino

ElDuderino

Posts: 1

December 29, 2015

Another clear example of how prizes pervert the execution of science.

It is sad that so many scientists lose their way and end up focusing their careers on building "monuments to self" (prizes, certificates, honorifics). Once a century a truly transcendant intellect -- an Einstein or a Feynman -- completely changes how we view the world. But, meanwhile, the rest of us toil as mere laborers at the forefront of research. We advance mankind's knowledge step-by-step, building on previous work of others. Making subtle distinctions to award prizes to one, and not the other, simply leads to acrimony. It is a perversion of all that is good about collaborative discovery. I say, let's eliminate prizes and societies. After all, it generally just spawns the worst of poilitics; the "winners" usually engage in a campaign to do so. The institutions that underly them, as Feynman once said, principally function to decide who to let in, and who to slight.

"Yeah, well, you know, that's just, like, your opinion, man."

Avatar of: joewalsh

joewalsh

Posts: 1

December 29, 2015

There is nothing new under the sun. Last year I wrote an article titled "The Jealousy of Scientific Men," that title being a quote from Darwin. It is available through your institution at 

http://abt.ucpress.edu/content/76/1/23

The article talks about some famous disputes for priority in science.

Joe

Avatar of: N K Mishra

N K Mishra

Posts: 58

December 29, 2015

 

The problem is that some researches are suppressed and others are highlighted for some ulterior purposes. These include getting grants, awards, and recognitions. There are reports that they swallow the findings of their juniors and later on regurgitate them as their own. The reviewers too feign ignorance about original contributors and tend to side with the senior ones.

Avatar of: dumbdumb

dumbdumb

Posts: 48

December 30, 2015

I am no expert in CRSPR/CAS, but for what I have understood so far, the fundamental credit of the technology goes to Doudna/Charpentier and all the researchers who lied the fundaments before them. Zhang, and apparently now Church, simply introduced an incremental improvment of the technology that would have been done anyway. If they wouldn't have the names Harvard and MIT attached to them, their claims would be dismissed as just delusional.

Church, in particular, looks really lame. He is so famous and powerful, and yet he still feels the need of approval like a spoiled little kid.

Avatar of: rschang

rschang

Posts: 1

December 30, 2015

Will The Scientist edit the original article to reflect this new bit of information? Seems appropriate.

Avatar of: tvence

tvence

Posts: 881

Replied to a comment from rschang made on December 30, 2015

December 31, 2015

Thanks for reading, rschang! TS editors chose not to alter the wording in the article that prompted this one. We have added an editor's note.

All the best,

Tracy Vence

News Editor, The Scientist

Avatar of: Caesar

Caesar

Posts: 1

January 2, 2016

A good reflection.

Yet it misses the 2005 papers alerting that CRISPR could be functioning as an immune system using the CRISPR transcript as a guide; By order of publication date: Mojica et al. (Feb), Pourcel et al.(Mar) and Bolotin et al.(Aug). These were the first descriptions of the mechanism of CRISPR/Cas system that gave rise to the CRISPR revolution. This is a huge miss.

By the way, iap is not a kind of repeat. It is a gene that codifies an alkaline phospatase. Ishino and colleges sequenced it and found in the vicinity the repeats.

Avatar of: MMicro

MMicro

Posts: 3

January 5, 2016

Basic science research discovers new knowledge and new systems be it in the biologicval   or physical sciences. Often the discoverers or others that understand the significance of these new discoveries utilize the new knowledge and APPLY it to new uses or to solve old problems. Credit is due to the original discovrers although those who utilize these discoveries often get the accolades and public recognition.

Who remembers that restriction enzymes and recombinant DNA technologies arose from work with bacteriophages lambda and P1 in E.coli?

Similarly, anti-sense RNA was identified during research on the control of plasmid ColE1 replication in  E.coli.  This is almosr never mentioned by those who use antisense RNA as major tools in eucaryote research.

Interestingly, CRISPR-Cas systems were originally discovered as part of bacterial defenses against phages and plasmids. In this case some of the discoverers went on to apply this new knowledge to engineer changes in various genomes.  Others will continue to fine tune the system to make it even more target specific and more widely applicable. These contributions will be essential to the eventual use of the system in human biology and should be credited but let's not forget that phage  and plasmid research started it all.

Avatar of: dant

dant

Posts: 1

January 7, 2016

Could we recall that McClintock didn't get her Nobel Prize until three dacades after her breakthrough. Why? Because she, like Frankin, were women. So, as we celebrate the breakthrough contributions of Doudna and Charpantier, let us recall that we are NOT giving them exclusive credit but rather exclusive recognition for how much they acconplished despite the burdens women bear. A 1990s DeptLabor study estimated that awoman does the equivalent of 28 full time jobs in our times. Girls seem to do 35% better than boys in high school, 70% better in college and even better in grad school, but somehow still need to walk a very steep planf from post-doc onward. Our society has always wispered under its sleeve that successful women will always abandon institutions because of childbearing and when they come back they will be of divided attention. This assumption has led to a bias that dictates not to encourage, not to entice and not to depend on their full effort. As a result, there is no question that while Doudna and Charpentier did not EXLUSIVELY make CASPR-Cas9 known to us, as women in our society, they STILL had to walk an incredibly steep side of the mountain of achievement in order to contribute that which they contributed along with all the rest who climed to the same height of Mount CRISPR-Cas9.

Our science community is still much more competitive than collaborative and so women are still considered one-lap-wonders who will never run to the goal. This has become as much a reason to deny them due consideration for their talents and mental capacities as ever, for in competition there is little "I help you through the rough times, you hel me, we all get there together." So the Doubna and Charpentier BREAKTHROUGH Prize is as much a statement of breakthrough for women multi-tasking as women always have to. It declares that collaborative women, who by nature beleive that "it takes a village" are recognized, not only for the accomplishments they bring to their field to achieve a breakthrough, but for the fact that the collaborative women's attitute of "it takes a village" is a path open to all, no matter what other burdens they bear. If we want the public to again support science as "open access," we had better recognize the accomplishments of the less competitive BECAUSE they are less competitive....and women certainly do tend to be more collaborative. So, recognition for Doudna and Charpentier is for, as they say themselves, the ability to collaborate over long distances without destructive competition, as so often happens in science (even to where ~1/3 of published papers have to be retracted for excessive competitive zeal), let us single out the women who, despite the dog eat dog of declining public support, make the best of it without running to the dark world of for profit science for funds. It's time to thank women for breakthroughs, not because they are unique or not equal to those of others, but because they broke through collaboratively rather than competitively. We can always give Prof. Church due recognition, as well as to all the others. But let us say to our wives and daughters that IF they do something great, we recognize how much of a breakthrough it is beacause they beat the odss without climbing over collegues. That, in the case of Doudna and Carpentier, is a model for our daughters we can all highlight as breakthrough...and all without denying the others their due.

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