Herbicide development has slowed in recent years, but innovative research methods could soon drive significant progress in the field.
For decades, the pace of discovery of new modes of action — that is, how a herbicide interferes with the plant’s normal functions — was robust. From the 1950s through the 1980s, an average of one new mode of action every two years was registered. Since then, aside from a smattering of new active ingredients, major herbicide innovations have become rare.
Dr. Franck Dayan, a professor in the department of agricultural biology at Colorado State University, pointed to several reasons for the decline, including increasing costs of research and development programs and commercialization. But Dayan, speaking at the Manitoba Agronomists’ Conference in Winnipeg, said one of the biggest reasons for the slowing pace of innovation is hubris.
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“For many years, we saw about 100 patents a year. Then, when glyphosate-resistant crops were introduced, that number suddenly dropped,” said Dayan. “We were told that glyphosate would solve all of our problems, so we stopped doing research in that area.”
The good news is, the slowed pace of discovery isn’t because researchers are running out of target sites for herbicides.
While it’s true that much of the low-hanging fruit has been picked, Dayan said scientists are still finding new target sites and new ways to exploit them more effectively.
Researchers are turning to new approaches — strategies that focus on previously overlooked biological pathways or that harness natural processes — to develop more effective herbicide solutions.
Targeting proteins for destruction
One exciting approach comes from a North Carolina company called Oerth Bio, exploring the use of PROTAC (proteolysis targeting chimera) molecules in herbicide development. A PROTAC molecule is a special type of molecule that helps an organism get rid of unwanted or harmful proteins — but they can also be fooled into targeting proteins the plant needs.
Traditional herbicides, Dayan explains, work by attaching to a specific protein in the plant, blocking its function, and killing the plant. Oerth Bio’s method is different: it uses the plant’s own systems to break down the target proteins.
Essentially, researchers identify a protein in the plant to target, then use parts of the PROTAC molecule to guide the plant’s natural protein breakdown system (E3 ligase) to tag the protein for destruction. The ligase attaches a small molecule called ubiquitin to the protein, marking it for destruction by the plant’s proteasome (a cellular “clean-up crew” that breaks down unwanted proteins).
“The beauty of this method is that it uses the plant’s own waste disposal system to remove targeted proteins,” Dayan says.
While Oerth Bio’s research is still in the early stages and not yet available commercially, it shows promise as a new way to target weeds by messing with their biological processes at the protein level.
Disrupting protein-to-protein interactions
Another promising strategy comes from the Israeli company Projini, which is tackling the challenge of what are known as “undruggable proteins.”
An “undruggable protein” refers to a protein in a plant that is difficult to target or affect with herbicide treatments because they lack the binding sites to which herbicides typically bind.
To overcome these challenges, instead of looking to disrupt traditional sites where a single protein completes a task, Projini targets biological processes in plants where two proteins must interact to complete a task.
Dayan pointed to an example where they identified compounds that prevent the two proteins involved in the synthesis of cysteine, a critical amino acid, from interacting. By disrupting these interactions, it’s possible to block entire biochemical pathways in the plant, preventing the production of critical compounds and ultimately killing the plant.
Doubling down on phosphonates
Another company pushing the envelope in herbicide development is MicroMGX, which focuses on discovering new phosphonates — chemical compounds with strong potential as herbicides. Glufosinate and glyphosate are both derived from naturally occurring phosphonates.
Phosphonates work by mimicking natural substances that plants need and disrupting their ability to process nutrients. For example, glufosinate mimics glutamate, a molecule that affects plant growth by interfering with an enzyme called glutamine synthetase.
To find new phosphonates, MicroMGX looks at the genomes of microbes to identify enzymes involved in producing these natural compounds. By screening a wide range of microbial strains, they’ve pinpointed a gene cluster in Pantoea ananatis, a type of bacteria.
Dayan says the Chicago company was able to retro-engineer this gene cluster, identify the structure of the phosphonate, and figure out how to grow the microbe to produce large amounts of a powerful, natural herbicide called pentafos.
Built-in resistance gene
Along similar lines, Dayan referenced a 2018 study published in Nature that uncovered some intriguing findings. The researchers focused on a compound called aspterric acid, produced by the aspergillus fungus, which has herbicidal properties. The researchers sequenced the fungus’s genome to identify the genes responsible for producing the herbicide compound.
The key point with this study is that, in addition to finding the genes for the herbicide, the researchers discovered another gene that gave the fungus resistance against its own toxic compound, allowing it to protect itself from the herbicide it produces.
“So you basically get a new herbicide and a new resistance target for that herbicide,” Dayan explains.
While these new technologies and approaches have led to a commercially available herbicide, they could become fruitful in the coming decades, and they could provide an abundance of new herbicides. But Dayan said the industry has learned from the overconfidence that surrounded the development of glyphosate-tolerant crops.
“Integrated weed management is still where we need to go,” he said. “If we keep doing the same thing we’ve been doing, we’re going to have the same problems over and over.”
