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Fighting the food crisis with gene-edited crops

There is considerable debate about how to regulate foods created using genome-editing technologies such as CRISPR/Cas9. Credit : Wang Yukun/Moment/Getty

As the world faces political instability, increasingly frequent extreme weather events, and a rapidly growing population, ensuring a sustainable, global food supply chain is of critical importance. In 2011, the United Nations’ Food and Agriculture Organization declared that production must increase by 60% if food security is to be ensured for 9.6 billion people by 2050.

“We need to use all the available advanced technologies to tackle this,” says plant molecular biologist, Hiroshi Ezura, of the University of Tsukuba, in Ibaraki prefecture, Japan.

The Food Cutting-edge Technology Joint Development Consortium, led by Ezura, is Japan’s leading hub for research into food security problems. Under the OPERA programme of the Japan Science and Technology Agency, 35 participating universities, public research institutes and companies are collaborating to develop next-generation genetic engineering and food production systems. To address consumer concerns about safety, the consortium has established a system where researchers are involved in commercialization and helping the public understand the benefit of new technologies through proof of concept.

Sicilian Rouge High GABA Tomatoes created using CRISPR/Cas9 technology.

CRISPR-edited food

One of the consortium’s short-term goals is to increase understanding and acceptance of GABA (ɣ-aminobutyric acid)-enriched tomatoes1 developed by Sanatech Seed, a University of Tsukuba spin-off company, for which Ezura serves as chief technology officer. The tomatoes attracted worldwide attention as the world’s first agricultural product launched on the market that were created using the Nobel prize-awarded CRISPR/Cas9 technology in 2021.

Numerous studies2 have suggested that GABA can help reduce blood pressure, but to realize these effects people would need to consume large quantities of tomatoes, Ezura says. The Sicilian Rouge High GABA Tomato produced by Sanatech Seed contains up to five times as much GABA as ordinary tomatoes.

Genome editing is a technology to pinpoint and rewrite targeted genes within an organism, without needing to introduce external genes. The technique itself has been around since the 1990s, but the CRISPR/Cas9 tool, invented in 2012 allowed for more speedy and efficient genome editing, accelerating its use in medical and industrial applications. The technology allowed Ezura to delete the autoinhibitory domain of a GABA-regulating gene which he identified during a decade of research on the biochemistry of tomatoes.

Different approach

The advent of the CRISPR/Cas9 sparked worldwide debates over how to regulate genome-edited foods. The European Union ruled in 2018 that genome-edited crops should be regulated in a similar way to conventional genetically modified (GM) crops which are made by the introduction of exogeneous DNA.

In 2019, the Japanese government took a different approach, stating that partial modification of genes wouldn’t be subject to regulations for GM food and biodiversity as long as they don’t contain exogeneous genes. In December 2020, Ezura submitted notifications of his GABA-enriched tomato to the health and agriculture ministries, and was given a green light to begin marketing3.

The EU recently relaxed its rules on genome edited-products, so competition in this space is expected to accelerate. So far in Japan, two kinds of fish developed using CRISPR/Cas9 are commercially available online, while another variety of tomato developed by Ezura’s team and a US-developed ‘waxy corn’ have been added to the lists. In the US, which has set similar rules to Japan, anti-browning lettuce and mustard greens with reduced bitterness — both developed through genome-editing — are commercially available.

Demand for the Sicilian Rouge High GABA Tomato increased after the Japanese Consumer Affairs Agency granted permission to label the product with functional claims, such as lowering blood pressure. In March 2023, the tomatoes became available in about 70 supermarkets in Tokyo and neighbouring regions.

Ezura’s success can be encouraging for many researchers striving to improve human health through genome-edited foods. Although the healthcare market is flooded with supplements, including GABA, “many people instinctively prefer taking nutrition through their daily diet, rather than depending too much on drugs and supplements,” he says.

The next step, he says, is to establish techniques to ensure a consistent quality and level of functional ingredients in crops, which are grown under varying conditions. As part of this, the consortium is working hard to develop AI-based smart cultivation techniques, Ezura adds.

Plant-based production of fluorescent protein GFP using the Tsukuba system.

Protein expression

Bacteria, yeast and mammalian cells have been widely used to produce complex proteins for vaccines and other pharmaceutical purposes as an alternative way to grow transgenic plants. These systems show higher expression levels than plant-based systems, but require costly investment.

To address this shortcoming of plant-based systems, the consortium has established the ‘Tsukuba system,’ a method which enables transient expression of useful proteins at a high yield in plants4. “Plants as protein expression systems are gaining much attention in recent years because they are low-cost, scalable and sustainable,” says Kenji Miura of the University of Tsukuba, one of the developers of the Tsukuba system.

For example, plant-based systems have been used to produce treatments for several conditions, including a genetic disorder called Gaucher’s disease, and a COVID-19 vaccine that was approved for use in Canada in 2022.

An agrobacterium-mediated system, or agroinfiltration, is an efficient method to express transient proteins in plants using a deconstructed virus as a vector. The most popular vector system, called magnICON, employs the tobacco mosaic virus which produces high yields, but its application is limited to a single type of tobacco plant.

Miura’s team instead picked a geminivirus vector as it can work in a number of host plants including lettuces, eggplants and tomatoes. But its expression levels were lower because the virus’ ‘rolling circle’ replication mechanism could cause transcription interference. Usually, there is one terminator section in a gene, but Miura’s team decided to add an additional terminator to reinforce the end of a single transcription.

“In that way, our Tsukuba system exceeded the yield level of magnICON in Nicotiana benthamiana in a short time and achieved comparable levels to expression systems in E. coli and other organisms,” Miura says.

Wider applications

The Tsukuba system has the potential to produce pharmaceutical proteins, Miura says. He is working with collaborators at other institutions to develop pollen allergens for use in immunotherapy, growth factors and diagnostic agents.

Another project is to apply the Tsukuba system to create genome-edited crops by transiently expressing enzymes to cut DNA, which could allow researchers to save time to create transgenic plants.

Miura also hopes to make the production cycle sustainable and eco-friendly. “Lettuces have a much larger biomass than tobacco. If we create a system to mass-produce proteins in factory-grown lettuces that would otherwise be discarded as substandard, we can not only achieve useful research outcomes but prevent food loss.”

For further information on the Food Cutting-edge Technology Joint Development Consortium, please visit its website.

References

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  2. Shimada, M. et al., Clin Exp Hypertens. 31, 342 (2009).

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  3. Ezura, H. Plant Cell Physiol. 63, 731 (2022).

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  4. Yamamoto, T. et al., Sci Rep. 8, 4755 (2018).

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