Pairwise sees ‘dramatic uptick’ in CRISPR licensing as gene editing moves beyond row crops

Gene editing is rapidly expanding beyond row crops into specialty crops, animals, and microbes, says Pairwise, which has seen a “dramatic uptick” in licensing deals for its Fulcrum platform over the past 12-18 months and now has 25 licensees covering more than 30 species. Unlike transgenic plants—which are classified as GMOs as foreign DNA from another species is introduced—gene editing involves tinkering with species’ native genes, which eases the regulatory pathway in a growing number of markets and can deliver speed and precision, two potential gamechangers in breeding, says COO Ian Miller, PhD. “We’re really enthusiastic about the direction that the regulatory environment is going worldwide,” adds Miller, who says Pairwise is seeing growing interest in Europe now that the EU has enshrined a new, simpler regulatory framework for plants made using new genomic techniques. “I think there’s an understanding that in many cases, what comes out from gene editing is equivalent to conventional breeding because we’re working within the plant’s own genes. The beauty of gene editing is that if it sits somewhere in the gene pool, you can bring it to bear for a problem.” Founded in 2017 by ag biotech veterans Tom Adams PhD, and Haven Baker PhD, alongside CRISPR pioneers and scientific founders Feng Zhang PhD, David Liu, PhD, and J. Keith Joung PhD, Pairwise has some high-profile collaborations with industry heavyweights such as Bayer and Corteva on row crops, spanning everything from short-stature corn to soybeans with reduced susceptibility to Asian soybean rust. However, its Fulcrum CRIPSR gene-editing platform is now attracting interest from a far wider range of companies, researchers, and nonprofits working on everything from cassava and cacao to insects, vegetables, ornamental horticulture, microbes used in ag biologicals, and livestock, says Miller. “I would say behind those 25 [licensees], I would say, we have at least as many more that are in various stages of discussion. We’re also working with a big CPG company that I can’t disclose yet.” Insects, microbes, livestock, plants… The breadth of those licensees gives Pairwise a window into where agricultural gene editing is heading. Agragene, for example, is using Fulcrum to work on sterile insects for pest control; Genus is working in animal genetics; and CSIRO—Australia’s national science agency—has a license covering livestock, aquaculture, microbes, and plants. Other licensees include vegetable seed company Enza Zaden and leading ornamental horticulture player Ball, while Mars has licensed the technology in cacao. Pairwise is also working with the International Institute of Tropical Agriculture (IITA) in yam and has licensed its technology for other staple crops including cassava, cowpea and rice. “I think if you look at the scope of the licensees there, it can go everything from yield to disease to composition,” says Miller. “We have other folks interested in biofuel.” For Miller, this breadth suggests there is considerable pent-up demand for genetic tools outside the handful of crops that have historically attracted most breeding and biotech investment. “It tells us there’s a lot of untapped potential.” The gene editing toolbox The easiest way to think about Fulcrum is to liken it to a word processor, Miller tells AgFunderNews: “We have Ctrl F to find the spot in the DNA to make the edit, and then we have tools that do everything from hitting the delete key [nuclease editing, typically cutting DNA to knock out or inactivate a gene responsible for an undesirable trait] to changing a letter [base editing, which chemically converts one DNA base into another without making a double-strand break]. “Then we have find and replace [templated editing, which uses a DNA or RNA template to rewrite a targeted stretch of DNA with a specified new sequence].” Pairwise routinely carries out multiplex editing internally and has performed as many as 17 simultaneous edits. IP licensing: ‘We want to make it easy for people to innovate’ Notably, Pairwise is trying to capture that opportunity by licensing a broad suite of gene-editing tools through a single platform rather than requiring users to assemble separate licenses from multiple IP holders, he explains. “You don’t have to get multiple licenses. We’re offering one-stop shopping. We license one stack, one royalty rate, which is competitive with what single licenses are charging folks in other spaces. The idea is whatever’s the right tool for the job, people should use. We want to reduce that friction and make it easy for people to innovate.” The business model typically includes a modest upfront fee, maintenance fees and royalties if a licensee ultimately commercializes a product. Pairwise can also provide limited technology transfer for customers that need help getting started. Perennial and specialty crops Two areas Miller sees as particularly attractive are perennial and specialty crops, where lengthy breeding cycles can make conventional crop development especially slow. The attraction of gene editing in perennials is partly speed, he says. “We can do things in a single generation that would take years and years and years to create. If you’re working in a tree in a breeder, and it takes you 5-10 years to do a cross, that limits your ability to innovate.” Blackberries are a case in point. A genetically complex perennial crop, they can be slow and challenging to improve through conventional breeding. Through gene editing, Pairwise has been able to develop varieties with a more compact architecture to triple plant density per acre, coupled with seedless and thornless fruit. “So the blackberry we’re commercializing ourselves with our partner Plant Sciences Genetics. They were the ones who did the original breeding on the variety that we edited on top of, but we’re actually the one taking that one to market, and we now have commercial growers for the compact variety in Colombia. “The pitless variety is in field trials right now,” adds Miller, who says Pairwise also has a partnership with Sun World International working on a pitless cherry. Miller does not see gene editing replacing conventional breeding, however. Rather, editing can create precise genetic variation that breeders can then work with, while conventional breeding remains useful for “moving large numbers of genes around.” The flywheel effect As work moves well beyond corn and soy, there’s less data to work with, acknowledges Miller, who says many crops have received a fraction of the genetics research invested in the major commodities. “Clearly, there’s been a lot less investment in some of these crops, particularly when you think about stuff that impacts the global South,” says Miller. But biological mechanisms can be conserved between species, he notes, enabling researchers to apply knowledge generated in better-understood crops to new ones. Pairwise’s work with IITA on yam provides one example. The partners are exploring a more compact plant architecture, drawing on Pairwise’s broader work on dwarfing and compactness in other crops, which creates a “flywheel effect” that increases the odds of success in subsequent projects, says Miller. “What we’re focused on is developing understandings of the networks of genes that produce traits. So dwarfing architecture is something we’ve spent a lot of time understanding, and so things may not be exactly the same from one crop to the next, but we do now have a much better understanding of those pathways.” There are limits, however. Editing tools can make increasingly sophisticated changes, but companies still need to understand which genes and gene networks control a desired trait, which is the biggest challenge with complex traits such as drought, heat or salinity tolerance. Ultimately, Miller sees Pairwise’s pipeline as evidence that CRISPR’s next phase in agriculture could look substantially broader than its first. “I’m wildly enthusiastic, and I think we’re in a great spot. What the shape of our pipeline tells you is that the opportunities for CRISPR in the future aren’t just focused on corn and soy.”