How CRISPR could yield the next blockbuster crop

By Michael Marshall

In the space of just a few years, Jiayang Li is trying to achieve something that once took people centuries. He wants to turn a wild rice species into a domesticated crop by hacking its genome. And he is already part of the way there.

Li, a plant geneticist at the Institute of Genetics and Developmental Biology in Beijing, is working on a wild rice species from South America called Oryza alta. It produces edible, nutritious grains, but they cannot be harvested because the seeds drop to the ground as soon as they ripen. To tame the plant, Li and his colleagues need to remove this trait, known as seed shattering, and alter a few others.

Li and his co-workers sequenced the O. alta genome and compared it with that of domestic rice, searching for genes similar to those that control important traits in the conventional crop, such as stem diameter, grain size and seed shattering. They then targeted these genes with customized gene-editing tools, trying to recapitulate some of the genetic changes that make domesticated rice easy to farm¹. All the traits improved to some degree, says Li, although the plants still drop their grains too soon. ″We are working on that,″ he says.

The modification of this rice is one of a growing number of efforts to rapidly domesticate new crops using genome editing. Through this process, known as de novo domestication, transformations that took the world’s early farmers millennia could be achieved in just a handful of years. The work might improve the resilience of the global food supply: many wild relatives of staple crops have useful traits that could prove valuable when climate change puts stress on global agriculture. O. alta, for example, has ″very sharp resistance to salt and to drought and to some very severe or very dangerous diseases″, says Li.

But the technical challenges of de novo domestication are immense. Most wild plants are understudied, and without an understanding of their fundamental biology it is impossible to domesticate them by rewriting their genomes. Targeted gene editing, using tools such as CRISPR–Cas9, is a powerful approach, but it cannot fully replicate the thousands of mutations that have fine-tuned modern domestic crops for growing and harvest.

″It seems like a very simple idea, but the more you start unpacking, the more complex it becomes conceptually,″ says plant physiologist Agustin Zsögön at the Federal University of Viçosa in Minas Gerais, Brazil. As a result, although commercial producers are interested in the concept, no companies are publicly pursuing it.

There are also concerns that de novo domestication could be misused. Many wild plants are well known only to Indigenous peoples, who have cared for them over many generations. Throughout history, colonial powers have stolen or exploited the knowledge of Indigenous peoples — as happened with the tea plant rooibos (Aspalathus linearis) in South Africa. ″I am very conscious of not repeating the mistakes of the past,″ says botanist Madelaine Bartlett at the University of Massachusetts Amherst.

There are proposals for how researchers could work ethically with Indigenous peoples and their knowledge, but so far these have not been widely adopted or codified into laws. ″In terms of food crops, we probably have largely ignored Indigenous communities,″ says botanist Nokwanda Makunga at Stellenbosch University in South Africa. ″People that are doing de novo domestication need to be more aware.″

Taming tomatoes

People have been domesticating plants for around 10,000 years. But domestication is a fuzzy concept, says Zsögön. Many plants can be grown to produce food, but they don’t match the predictability and yields of commonly cultivated crops, such as maize (corn) or potatoes, and they are not as easy to harvest. A useful rule of thumb is that domesticated species have developed a permanent relationship with humans. If they are left to their own devices they might wither, fail to propagate or simply lose the traits that humans value over a few generations.

Although there is no written record of the first domesticated plant species, it is clear that they were generated — intentionally or not — through breeding that selected for desirable traits, such as large fruits or a lack of toxins. Over many generations, the mutations that control these traits accumulated, resulting in crops that were very different from the ancestral line. For instance, the large, soft kernels of modern maize look almost nothing like the small, hard seeds of its wild ancestor, teosinte.

Wild (left) and domesticated South American tomatoes, Solanum pimpinellifolium. Credit: Agustin Zsögön

Selective breeding is still a mainstay of agriculture. But breeders now target specific traits and often use mutation-causing radiation or chemicals to speed up the process of creating genetic variants.

Despite these advances, many of the methods for introducing traits to crops or producing entirely new crops rely to some extent on chance. Breeders have no way to control what mutations arise. Instead, they must create large numbers of mutants and carefully screen them, in the hope of finding the few useful mutations among thousands of harmful ones.

Gene editing promises to change that, by allowing researchers to edit the genomes of organisms in a targeted way. Geneticists have been doing this for decades by using established methods for adding entire genes to organisms to create ‘transgenic’ crops such as insect-resistant or herbicide-tolerant maize or soya bean plants. But new gene-editing tools provide much more control, allowing researchers to precisely edit the existing genome at chosen sites. The most prominent technique uses CRISPR–Cas9, which was originally part of the ‘immune system’ of bacteria and can be reprogrammed to edit genomes².

The first demonstrations of de novo domestication through genome editing happened in 2018. In one, Zsögön and his colleagues domesticated wild South American tomatoes called Solanum pimpinellifolium. They are the closest wild relatives of domesticated tomatoes (Solanum lycopersicum). The fruits of S. pimpinellifolium are small, even compared with cherry tomato variants, but edible. ″They are sweet and sour with a hint of spiciness,″ says Zsögön. His team edited six key regions of the plant’s genome to produce a version that resembled a domestic tomato. The new plants produced ten times as many fruits as the wild plants did, and the fruits were three times the size³.

In another study⁴, a team led by Zachary Lippman at Cold Spring Harbor Laboratory in New York and Joyce Van Eck at Cornell University in Ithaca, New York, took a wild groundcherry (Physalis pruinosa) a few steps closer to domestication. Groundcherry belongs to the same family of plants as tomatoes, potatoes and peppers. It is grown in parts of Central and South America for its sweet, golden berries. But harvesting it is difficult because of the plant’s sprawling growth and because the fruits are small and drop to the ground quickly once they ripen. The team modified one gene called Ppr-SP5G to make the plants more compact, and tweaked another, Ppr-CLV1, to make the fruits 24% heavier.

These were dramatic breakthroughs, but the new plants are not yet being grown on a large scale, let alone being sold to consumers. Although that is the ultimate goal, these first studies were ″a proof of concept″, says Zsögön. ″We just showed that it could be done.″

He says that de novo domestication should be particularly useful for creating crops that can resist non-biological stressors such as drought, because the relevant traits often involve multiple genes; breeding each one into domestic species would be enormously time-consuming. With de novo domestication, researchers could, theoretically, take the wild plant and quickly domesticate it by tweaking a handful of genes.

Some wild species also use nutrients such as nitrogen more efficiently than do domesticated varieties, says Li. The domestication of wild plants should allow farmers to use less fertilizer, reducing costs as well as harmful run-off into rivers.

These potential benefits have spurred multiple groups to attempt domestication projects.

In 2018, molecular geneticist Sophia Gerasimova started trying to domesticate wild potatoes while at the Siberian Branch of the Russian Academy of Sciences in Novosibirsk. In 2022, she moved to the Genomics for Climate Change Research Center in Campinas, Brazil.

Gerasimova and her colleagues screened wild potato genomes looking for a good candidate species. To be suitable for domestication, a plant had to be amenable to CRISPR and have potentially useful traits. If the plant had ‘bad’ traits, these needed to be controlled by a small number of genes. The wild potato they eventually settled on, Solanum chacoense, had many appealing properties: it produced round tubers that looked like domestic potatoes, was resistant to viruses and pests, and the plants were easy to work with because they were neat and compact. It was also resistant to ‘cold sweetening’ — the tendency of some potatoes to become rich in glucose and fructose when stored in the cold, leading to an unpleasant taste when cooked. However, the tubers were ″small and bitter″, says Gerasimova. They needed to fix that.

Gerasimova and her colleagues identified five target genes for CRISPR editing, which they think are involved in crucial traits such as the timing of tuber formation and the accumulation of toxic steroidal glycoalkaloids⁵. However, the researchers have struggled to make the necessary edits to the plants. Gerasimova says that they have succeeded in editing the genome in plant cells, but have not yet managed to get these mutations to propagate to an entire plant. She is optimistic that they will overcome this hurdle.

Researchers are editing the genome of a wild groundcherry to aid harvesting. Credit: Getty

There are a host of reasons why de novo domesticated crops are not yet being grown commercially. One is that, as Gerasimova’s experience illustrates, applying CRISPR to a new species is a challenge in itself.

Equally important is the complexity of domestication. Although it’s true that a handful of genes can cause marked changes, domesticated crops differ from their wild relatives in many regions of their genomes, and each difference can have a small but important effect. ″There are many thousands of genes that contribute to making corn different to teosinte,″ says Bartlett. It’s not practical to use CRISPR to reproduce all these changes.

So, conventional breeding techniques will continue to have a large role. Developmental biologist David Marks at the University of Minnesota in St. Paul is part of a team working to domesticate field pennycress (Thlaspi arvense) as part of his institution’s Forever Green initiative. Pennycress has a single vertical stem, with small cabbage-like leaves and white flowers. Its seeds contain a useful oil, ″extremely similar to canola oil″, Marks says.

The entire domestication project has relied on mutagenesis and selective breeding — conventional methods that Marks notes are still being improved and are now much faster than in previous decades⁶. By the time CRISPR took off, the project was already at an advanced stage.

″Don’t get me wrong,″ says Marks. ″The CRISPR technique is elegant, beautiful and simple. I wish like hell it was available back in my early days.″ However, it is practical only in certain circumstances. ″In the case of pennycress, we’re starting off with a plant that already has desirable characteristics,″ he says. The single-gene changes achievable with CRISPR were not needed. But many other potentially useful wild plants, such as O. alta, need these kinds of targeted changes in a small number of genes.

Fundamental gap

There is one further obstacle to de novo domestication by gene editing, and that is botanists’ limited knowledge of wild-plant biology. Much of what is known about plants comes from a handful of model species, such as thale cress (Arabidopsis thaliana). Most wild plants have not even had their genomes sequenced, let alone been subject to the intensive study required to learn what the DNA sequences do, which is necessary before de novo domestication can be attempted. ″You have to have basic information and the basic building blocks in order to be able to do this manipulation,″ says Makunga.

″The technologies have far outpaced our knowledge of the fundamental biology,″ says Bartlett.

Another complication is finding ways to account for the rights of Indigenous groups. Bartlett and Makunga argue that these communities need to be included in any de novo domestication programme from the start⁷. ″We need to be much more ethical in our practice,″ says Makunga.

When Indigenous people have a claim on a wild plant, ″they should be involved in those projects and benefit from any sorts of innovations that emerge from them,″ says Maui Hudson at the University of Waikato in Hamilton, New Zealand (see also ref. ⁸).

South Africa has taken steps in this direction. Makunga and her colleagues have met with representatives of the San people to discuss the benefits of a new project — something that they were required to do under South Africa’s National Environmental Management: Biodiversity Act 10 of 2004. The 2010 Nagoya Protocol, part of the Convention on Biological Diversity, also requires that benefits from the use of genetic resources are shared with Indigenous groups. Likewise, Brazil has created a repository for all research that involves native species, and a mechanism to compensate Indigenous communities if their knowledge leads to a profit. Zsögön does not expect his projects to trigger this mechanism because the plants he works with grow widely. Similarly, the rice Li works on is ″widespread in South America″ and ″is not tied to any particular Indigenous group and has not been cultivated by anyone anywhere in our knowledge″.

However, arrangements such as those in Brazil remain rare. For example, South Africa’s commercial rooibos tea industry has existed for more than a century. The plant is only weakly domesticated, so the industry is only possible thanks to Traditional Knowledge preserved by the Khoi and San peoples. Yet it took until 2019 for the industry to sign an agreement that requires it to pay Khoi and San communities.

Despite the challenges, both technical and political, researchers are enthused about the potential of de novo domestication. ″I’m excited by a future where we have customizable and modifiable plant development,″ says Bartlett. ″I think that that is actually a prospect that we might see in my lifetime.″

Nature 625, 230-232 (2024)

doi: https://doi.org/10.1038/d41586-024-00015-w

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