Since its introduction in 2012, CRISPR-based genetic engineering technology has transformed biotechnology and opened new possibilities in biomedicine. Currently, CRISPR is driving development in yet another domain—agriculture. Although CRISPR has been slower to realize agricultural applications than biotechnology and biomedical applications, it is ready to help us cope with an array of agricultural challenges that includes an expanding population, a rapidly warming climate, and a shrinking supply of arable land.
Nearly a decade after Charpentier and Doudna’s landmark study demonstrating that CRISPR systems could be programmed for targeted DNA cleavage in vitro (Jinek et al. Science 2012; 337(6096), 816–821), scientists have started to make good use of CRISPR systems in agricultural biotechnology (agbiotech). In fact, the first genome edited agricultural product has already hit the market in Japan. This product is a tomato called the Sicilian Rouge High GABA. It was engineered by Sanatech Seed, and it is meant to help consumers reduce their blood pressure. If this product does well, it may encourage other agbiotech companies to ramp up their own CRISPR genome editing programs.
CRISPR has both practical and regulatory advantages over traditional plant breeding and genetic modification methods. Consequently, CRISPR is looking increasingly attractive to agbiotech companies that hope to engineer products that can improve human health and the environment.
Enhancing genetic variability
CRISPR-Cas9 technologies can help product developers accomplish tasks that would severely test or simply exceed the capabilities of traditional plant breeding technologies. For example, CRISPR-Cas9 technologies excel when product developers need to enhance genetic variability.
“It’s all about genetic variability,” affirms Sam Eathington, PhD, the chief technology officer at Corteva Agriscience, one of the Big Four seed companies. “In some crops, we don’t have as much variability as we’d like. There are times that variability is locked up in parts of the genome that you just can’t unlock easily. Or you bring in a gene for improved disease resistance from a wild species that can intermate, but you bring along a whole bunch of stuff that’s detrimental.” CRISPR can overcome those obstacles, accessing that variability while removing unwanted baggage.
Corteva was formed in 2019 from entities—DuPont Crop Protection, DuPont Pioneer, and Dow AgroSciences—that had been part of DowDupont. (What remained of DowDupont is now simply Dupont.) Today, Corteva maintains plant breeding, biotech, and chemistry capabilities inherited from DowDupont, and uses these capabilities to develop products with improved traits such as oil profiles, amino acid composition, or disease resistance.
A key challenge faced by Corteva (and other companies) is an uncertain regulatory environment. In the United States, regulations were instituted in 2020 that ease restrictions on genetic engineering of food crops. The new regulations target the traits rather than the technology used to create them. Some gene edited plants are exempted from oversight altogether. Specifically, plants aren’t subject to regulation if the changes made to their genomes could have been created through traditional breeding alone.
Conversely, in 2018, Europe imposed the same regulations on gene edited crops that have restricted conventional genetically modified crops since 2001. Last April, however, the European Commission released a study that could lead to an easing of restrictions on gene edited crops. The report finds that CRISPR tools are compatible with existing European crop sustainability initiatives, and that the 2001 regulations governing GMOs are not suitable for addressing the new genome editing technologies.
This report raises hopes that the European Union will, like the United States, adopt a policy that considers most gene editing technology for plants to be equivalent to plant breeding technology. This transition, however, could take a couple of years, according to Eathington, who indicates that in the meantime, progress in agricultural applications of gene editing technology have been slowed worldwide because Europe, which imports large amounts of grain from overseas, refuses food and feed that has been produced by genetically modified organisms (GMOs).
“We can play within the process once we understand the process,” Eathington remarks. “If CRISPR has a more favorable regulatory situation, and is treated more like plant breeding, that will accelerate innovation in agriculture.”
Although gene editing has many advantages, Eathington notes that CRISPR-Cas9 and other gene editing tools come with some limitations. One of those is that editing works only with the genetic variability that exists within the plant. For example, Eathington says, the introduction of Bacillus thuringiensis (Bt) genes into crop plants for pest resistance would be difficult or impossible to accomplish using gene editing.
Building on synthetic biology
One other major challenge in genome editing for plants and crops is knowing what genes and combinations of genes to edit. Plant genomics is light years behind human genomics when it comes to the availability of functional genomic data. That’s a problem Yield10 Bioscience is hoping to solve.
The company used to be known as Metabolix. Back then, it engineered microbes to make bioplastics. However, in 2015, the company rebranded as Yield10 and shifted its focus to crop science. Today, Yield10 develops technologies to meet food production demand, which is forecast to increase 70% over the next 35 years. Specifically, Yield10 leverages bioinformatics tools and genome editing to optimize plant photosynthetic efficiency and directed carbon utilization.
“[We’re able to] precisely change either a single gene or multiple genes simultaneously in a real crop,” says Oliver Peoples, PhD, Yield10’s CEO.
Yield10 has developed a suite of tools. Its GRAIN (gene ranking artificial intelligence networks) platform is designed to identify combinations of plant gene modifications to improve crop performance, especially yield. Through a research collaboration with the Broad Institute of MIT and Corteva, Yield10 is also using CRISPR genome editing technology to enable step-changes in plant yields and other valuable performance traits.
“What we bring to this space is a completely different background based primarily on synthetic biology,” Peoples asserts. That background includes 30 years of experience engineering microbes. When the focus of the industry shifted to renewables and recycling, rather than bioplastics, the company pivoted to bring its experience to optimizing food crops, using Camelina sativa as a model organism to develop the technology. The company is also producing polyhydroxyalkanoate (PHA) bioplastics in field-grown camelina plants. These bioplastics may be suitable for manufacturing a wide range of fully biodegradable consumer products.
Yield10 aims to apply its GRAIN platform to develop its own product pipeline. The company is licensing the platform and collaborating with other companies in the agbiotech space to identify genes that could be targeted to improve the performance of crops such as soybean, forage sorghum, and potato. Yield10 has a research partnership with United Kingdom–based Rothamsted Research to develop an omega-3 fish oil substitute in camelina.
Changing the face of plant development
Benson Hill is another company taking a data science approach to target identification for plant genome editing. Its CropOS technology is a machine learning application designed for phenotyping, predictive breeding, and environmental modeling. Jason Bull, PhD, Benson Hill’s chief technology officer, says the company uses CropOS across all stages of product development, from design, to building crop prototypes, to product testing.
“It both guides our actions and is fed by all of the actions we take,” he adds. “It’s an iterative cycle. Every time we go around the cycle, we generate more data. That data is fed back into CropOS, and the predictions become more accurate.”
According to Bull, the typical product development cycle for GMO products can take 10 to 15 years, from beginning to commercial introduction. But if an approach like CropOS is used, and if it is combined with genome editing, development timelines can be cut by one-half or even two-thirds. “It’s exciting,” Bull says, “because it opens the field up to a lot more players beyond the traditional big agricultural companies.”
Bull indicates that Benson Hill is using its stacked bioinformatics and genome editing approach to restore qualities of protein content, functionality, and flavor that have been lost in soybeans through successive generations of breeding for yield. The company is pursuing similar goals with yellow peas, which Bull calls one of the fastest emerging crops in the protein market. It is also working with tomatoes, optimizing flavor and developing nutraceutical applications. Bull declares that these kinds of food crop improvements could be coming very rapidly: “You start stacking these technologies in your toolbox, and it really changes the face of plant development from what it has been for the last 20 or 30 years.”
Cultivating sustainable forests
CRISPR technology in agbiotech is not limited to food crops. It is also being used to improve forest trees. For example, CRISPR technology is being combined with insights from tree genetics by TreeCo, a new company to enhance tree traits that are valuable to the timber, chemical, and fiber industries. TreeCo’s founders, Rodolphe Barrangou, PhD, and Jack Wang, PhD, say that the company is also using CRISPR technology to benefit the environment.
“I’ve had the great privilege to see this technology revolutionize genetics in a number of contexts and applications,” Barrangou states. “There’s nothing more fitting than using and harnessing the tremendous power of genome editing, not just for therapies and disease, not just for crop and livestock, but to breed a better, healthier, and more sustainable forest.”
TreeCo is working on improving commercially important trees such as poplar, eucalyptus, pine species, and hemlocks—including an endangered hemlock native to the Appalachian Mountains. Barrangou says that TreeCo’s portfolio reflects the company’s emphasis on traits such as pest resistance and drought tolerance over traits such as yield and height. TreeCo is working to develop trees amenable to pulping for the fiber industry.
“We’re really working on chemical composition enhancement as a phenotype of interest,” Barrangou points out. Such enhancement, he continues, can lead to an industry that is more efficient and more sustainable, and that has a lower carbon footprint.
In the case of trees, the gulf between traditional plant breeding methods and CRISPR could not be greater. Tree breeding through classical methods is slow and challenging, as each generation of trees requires many years to mature, meaning an individual scientist could only breed three to four generations of trees in a lifetime. That means progress with trees has been glacial compared to that with most annual crops. But now, CRISPR systems make it possible to edit tree cells, and the trees can then be grown in a greenhouse. With the CRISPR approach, the time needed for tree breeding can be decreased as much as 10-fold.
Forestry applications are very different from conventional agbiotech applications. According to Wang, most of the forests around the world are dominated by wild, undomesticated tree variants, and in these forests, few if any genetic improvements are observed. However, he says that CRISPR can expedite genetic improvements, resulting not just in better trees, but also better forests. “There are,” he insists, “tremendous opportunities for CRISPR to enhance these very important natural resources.”