RNAi-based pesticides contribute to the promise of a New Green Revolution

By Michael Helmstetter

Farmers sow. Plants grow. Insects eat. Plant pests have been a fundamental challenge to farming since the beginning. Farmers have used a variety of methods for thousands of years to control the pests. Early chemical pesticides were derived from plants, animals, or minerals, from the extract of hellebore plant used by the Romans in 100 B.C.E., to the application of arsenic by Chinese farmers around 900.  

In the 1940s, modern chemistry delivered new classes of man-made chemical pesticides that still are widely used today. These synthetic chemical pesticides were important enabling tools for the first “Green Revolution” that started in the 1950s as a result of efforts by agronomic scientists, including Norman Borlaug (who won a Nobel Peace Prize in 1970), and significantly contributed to saving billions of people from starvation. They continue to be important in maintaining crop productivity in modern high-efficiency agriculture systems, but there are downsides to heavy reliance on chemical pesticides. 

One is that insects and other pests evolve resistance to commonly used pesticides. This complicates pest management strategies for farmers and can result in lower crop yields and higher operating expenses. Another challenge is that many chemical pesticides can exact a steep environmental cost, including contaminating water and negatively impacting beneficial insects – such as honeybees – along with wildlife and humans. Consumer demand and regulatory bodies in many parts of the world, including the United States and European Union, are moving to limit or eliminate use of certain chemical pesticides.

In response, the farming industry is entering a “New Green Revolution” that draws on a system of innovations to enable efficient, effective, and profitable farming practices while minimizing negative environmental and human health consequences. A key component toward that end is the development of new pest control solutions. A new class of pesticides, RNA interference (RNAi) pesticides are poised to become one such important tool in the world of pesticides and provide farmers with attractive choices for their integrated pest management strategies.

The Time is Now for Genomics-informed RNAi Pesticidal Solutions

Knowledge of RNA interference is relatively new. In 1998 the American scientists Andrew Fire and Craig Mello first published their discovery of RNAi. They would go on to receive the 2006 Nobel Prize in Physiology or Medicine for their work. RNAi is a natural cellular process in fungi, plants, animals, and humans that has the function of disrupting or “silencing” the production of a specific gene product, such as a protein, to maintain normal growth and function.  

RNAi promises advantages as a pesticidal class: it is effective, efficient and can be designed to target a specific pest. To understand how, first consider today’s chemical pesticides, which are generally designed to bind to an important protein in the pest, thereby disrupting the protein’s activity and killing the pest. But proteins are large, complex three-dimensional structures, and designing a chemical pesticide with specificity to a single target pest is extremely difficult. Thus, most chemical pesticides are highly effective but not pest specific – they are harmful to a wide spectrum of species, often including animals and humans.

In contrast to chemical pesticides, RNAi functions to prevent an essential protein from being made in the first place. Now for a little science…RNAi pesticides disrupt a targeted step in the process in which genetic information stored in the organism’s DNA is translated to make a protein. The molecule that RNAi insecticides binds to is messenger RNA (mRNA), an intermediary molecule in the transfer of information from DNA to the protein. An mRNA molecule contains the “instructions” for how to make a particular protein. So, designing an RNAi to recognize and bind to a specific region of an mRNA just in the target pest, but not in organisms you want to protect, is achievable, particularly with the vast array of modern genomics tools and data available to us today.

Scientists have been working on the development of RNAi pesticides for several years. In 2017, Monsanto Co. received U.S. Environmental Protection Agency (EPA) approval for an RNAi targeting the important insect pest corn rootworm. Monsanto elected to deploy this RNAi insecticide as a transgenic trait in the corn plant. The GMO corn plant itself made the RNA, so when a corn rootworm fed on the corn plant, it would also eat the RNAi insecticide and the worm would die.  

Monsanto’s decision to generate the RNAi insecticide as a transgenic trait versus a sprayable pesticide made sense due in part to the high cost of manufacturing an RNAi insecticide at that time. In 2017, production of RNA was expensive, costing a minimum $600 per gram, often much more. Given that of 1-5 grams of RNA would likely be needed per acre for efficacy, and farmers typically pay in the $15-$25 per acre range for a chemical pesticidal application, the concept of using RNA as the active ingredient for a field-applied pesticide was commercially infeasible. 

Since then, several approaches have dramatically driven down the price of RNA production – some promising to achieve a cost of $1 or less per gram. This low price point now makes it commercially feasible to develop RNAi pesticides as a farm production tool.

There are now several companies producing inexpensive RNA. Our portfolio company RNAissance Ag recently acquired one of the players in the RNA production space, RNAgri. This technology is attractive because it uses an industrial fermentation bacterial species that is commonly used to manufacture food and feed ingredients and is considered by the USDA to be “generally recognized as safe,” can be cost-effectively produced, and is promising for control of many plant pests.   

The combination of cheap RNA with the excellent genomic resources available makes field application of RNAi pesticides now feasible where it was not before. This opens up an attractive new mode of action to the agricultural pesticidal market. RNAissance Ag’s first field trials for its RNAi insecticide targeting the important pest diamondback moth are currently underway.

Additional Uses for the Emerging Availability of Inexpensive RNA

In addition to developing RNAi-based pesticides for commercial farming use, there are also attractive potential applications for home and garden use, including targeting termites and ants. The very safe nature of an RNAi pesticide should have appeal for domestic use. In addition to pests, there is evidence that RNAi may also be effective as a fungicidal agent. Plant fungal disease is a major agricultural problem, many of the existing fungicides are highly toxic, and a number of them are now banned or are on a path to be banned in some geographies. It is possible that RNAi may also be developed as a plant antiviral agent (yes, plants get viruses too).  There are promising results using RNAi to promote honeybee health by targeting viruses and the damaging varroa mite.

RNAi may also have applications for animal health. For example, work by RNAissance Ag and others is underway to develop RNAi antiviral agents for shrimp health, including targeting white spot syndrome virus, a major shrimp viral pathogen. There is also promise of RNAi antiviral and other indications activity for other animals including fish, poultry, pigs, and cattle.  

There are many challenges facing plant agriculture and animal health that might be addressed with RNAi technologies. The combination of vast genomic resources at our fingertips with the ability to manufacture RNA at low cost opens the door for the development of multiple product types that simply were not feasible even five years ago. 

The future is indeed bright and growing for RNAi.