Nobel-winning CRISPR scientists are fighting for its patent | #students | #parents

This week Jennifer Doudna and Emmanuelle Charpentier were awarded the Nobel Prize in chemistry for developing a process to edit DNA known as CRISPR Cas-9. But the announcement, which comes amid a years-long battle over who owns the methodology to make genomic edits, is bittersweet.

CRISPR Cas-9 is based on an immune system response in bacteria that literally cuts out invaders. In the last decade scientists, including Doudna and Charpentier, have figured out a way to repurpose the same function to edit out undesirable genetic mutations. The discovery has sparked a lot of hand-wringing over how the technology will evolve and the ethics of using such a tool to create perfect humans.

Doudna and Charpentier met at a conference in 2011 when Charpentier, an expert in bacterial systems who had published on CRISPR, was working at Umea University in Sweden. Doudna was a biologist at the University of California at Berkeley with a budding interest in the system. In their first year working together, they published a paper laying out how to use CRISPR Cas-9 to make changes to DNA. Doudna went on to publish a paper in 2013 using the same technique to make gene edits in animal cells. But Feng Zhang, a scientist at the Broad Institute, MIT’s genomic research center, had published a similar paper four weeks earlier, making him the first to prove the tool could be used in human cells. This was the beginning of what has become a years-long legal battle over who owns the CRISPR Cas-9 editing system.

The current litigation is over conflicting patents that lay claim to the use of CRISPR Cas-9 to edit genes in human cells. The University of California at Berkeley and the University of Vienna were the first to file patents on the gene-editing process, but the Broad paid to fast-track its patent review. In 2014, the U.S. Patent and Trademark Office awarded several patents to the Broad. A party led by U.C. Berkeley subsequently filed an interference claim. The Patent Trial and Appeal Board is still in the process of determining which party was first to invent the editing framework.

The argument over who gets to profit from CRISPR has been extremely public, a function of how game-changing the initial discovery was. At the heart of the argument is whether or not it was clear that Doudna’s and Charpentier’s method would work in human cells. This has been the subject of both the litigation over CRISPR Cas-9 and debate among scientists.

[Illustration: © Johan Jarnestad/The Royal Swedish Academy of Sciences]

Rewriting history

The debacle has showcased how nasty the science world can get. In 2016, the Broad’s president and founding director, Eric Lander, published an article in the scientific journal Cell that was at best opportunistic and at worst an attempt to control the historical narrative around CRISPR Cas-9. It was called “The Heroes of CRISPR.” The title alone connotes that men are responsible for the various discoveries around enzyme-based gene editing, and unsurprisingly, the article focused on the men behind CRISPR. The article casts the Broad’s Feng Zhang as the hero who discovered CRISPR Cas-9’s editing capabilities in human cells and significantly downplays the roles of Doudna and Charpentier.

After it came out, three of the scientists mentioned in the story put out statements that Lander’s story was inaccurate. For many scientists speculating on the sidelines, the story served as an egregious example of how the history around science can be shaped by powerful people who have the potential to profit—a structure that often leaves women out of the glory. Only seven women, including Doudna and Charpentier, have ever won the Nobel in chemistry since the prize was first awarded in 1901. For some, the Cell piece was especially stomach-turning because it diminished the work of the two women under the guise of giving credit to all the scientists who had done work involving CRISPR.

The story also highlights how the politics of turning science into a for-profit venture is becoming more powerful than the science itself. As Michael Eisen, a biologist at U.C. Berkeley, put it at that time, the business of science is increasingly becoming a part of the scientific process, where experiments, papers, and discoveries are being used to further commercial ends rather than scientific ones. “The most worrying trend has been the willingness of some researchers and research institutions to distort history, demean their colleagues, and misrepresent the scientific process to support these efforts,” he wrote.

Nobel’s choice of Doudna and Charpentier seems to refute that trend, illustrating that science can prevail over politics. Though the women’s findings are widely regarded as an enormous leap forward in gene editing, the prize cements their research as pivotal. The two were also awarded a Breakthrough Prize in 2015 from a board of tech industry luminaries for their work.

But some scientists are a little uneasy about who Nobel didn’t acknowledge. The award left out other scientists who contributed work leading up to the CRISPR Cas-9 breakthrough, including a Northwestern University postdoctoral student named Luciano Maraffini, who showed that CRISPR targets DNA in 2008. This is ultimately what is complicated about awarding any one entity claim to a scientific discovery: Science is iterative and relies on the work of many.

CRISPR’s uncertain future

While the Nobel award certainly affixes Doudna and Charpentier’s place in history, the ongoing litigation continues to hang heavy over the development of CRISPR Cas-9’s editing capability. Some scientists feel that with so much public money involved in discoveries such as the ones around CRISPR Cas-9, no one should have a right to the intellectual property. This would keep the science open and allow others to innovate on top of it without the fear of litigation or the sometimes high costs of royalties. Meanwhile, investors, ever aware of the legal landscape, are looking to finance new biotechnology that doesn’t infringe on the existing CRISPR patents.

“We’re mindful that that litigation is going to have an impact on the freedom that our companies have to operate in,” says Paul Conley, a managing director at venture capital firm Paladin Capital Group. “We try to remain agnostic by finding the companies who are using CRISPR machinery—these nucleases—that definitely don’t tread on any of the IP that’s being litigated.”

That litigation hasn’t entirely stopped CRISPR exploration. In fact, a whole industry of apparatuses and chemicals has emerged to facilitate CRISPR gene edits. CRISPR Cas-9 is showing promising results as a treatment for rare diseases such as sickle cell anemia as well as an implement for biomanufacturing. But the litigation may be shifting gene-editing research. Like any technology, CRISPR Cas-9 is not perfect. It’s not as precise as some scientists would like, and it can have unanticipated effects outside of the desired outcome. Scientists who don’t already have a claim to the CRISPR Cas-9 system may be more inclined to seek out other gene-editing opportunities rather than improve Cas-9. Conley says scientists may be wary of pushing the technology ahead.

It has absolutely put fear in the minds of many scientists who frankly could do great things for society.”

Paul Conley

“It has absolutely put fear in the minds of many scientists who frankly could do great things for society,” says Conley. “They are living in terror of, well, if I go down this road a) am I going to be sued? And b) is there any commercial outlet where I’m going to have trouble raising money, because there’s fear and loathing around the CRISPR component?”

Much of the new science surrounding CRISPR Cas-9 has come from scientists with a stake in the intellectual property. Last year, David Liu, a scientist at the Broad Institute and cofounder of gene-editing therapeutics company Editas Medicine, published a way of making more precise edits with fewer unintended effects using a new process called prime editing. One of Doudna’s companies, Scribe Therapeutics, is engineering CRISPR molecules, rather than using the ones found in nature, in order to do away with the natural aspects that get in the way of putting it to good use as a targeted gene editor. The company just raised $20 million and signed a deal with pharmaceutical company Biogen to implement its technology.

Meanwhile, many researchers are seeking alternative gene-editing mechanisms, whether because of the litigation or because of the imperfection of CRISPR Cas-9 itself. There is an effort to find enzymes that perform many of the same cutting functions as the Cas-9 protein but are less entrenched in a legal morass. Conley thinks that eventually this avenue of research will push gene editing far beyond what CRISPR Cas-9 is capable of.

“When history gets written, this will be an interesting paragraph in that history book,” says Conley. “I think inevitably as an industry gets built on CRISPR and whatever comes after CRISPR, I think this food fight will be an interesting footnote overshadowed by the game-changing things that are coming to market.”


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