Crop Protection: The Fall & Emergence Of RNAi

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In our first edition, we're thrilled to dive deep into the fascinating world of RNAi and its applications in agtech. For this edition, I interviewed the CEO & co-founder of Trillium Ag, Todd Hauser, a seasoned biotech and gene-silencing entrepreneur.

So sit back, relax, and get ready to explore the exciting world of agtech with AgTech News®!

Where It All Started: The Early 2000s & The Nobel Prize Awarded To American Scientists Andrew Fire and Craig Mello

In 2006, two scientists, Andrew Z. Fire, and Craig C. Mello won the Nobel Prize in Physiology or Medicine for discovering RNA interference (RNAi). RNAi is a process that can turn off specific genes in cells. This is important because it helps scientists study how genes work and could help develop new disease treatments.

Fire and Mello discovered RNAi by studying tiny worms called Caenorhabditis elegans. They found that small pieces of a double-stranded RNA molecule called siRNA could turn off specific genes in these worms. This discovery opened up a new area of research to study how genes work in many living things, from plants to humans.

The discovery of RNAi has enormous implications for human health. It could potentially be used to treat many different diseases, including cancer and genetic disorders. It has also helped scientists identify which genes are implicated in disease pathways and find new drugs to treat those diseases. Beyond the application in the pharma industry, it can also be used in agriculture. The same principles can potentially be applied to combat pest infection (Insects, fungi, weeds, or bacteria).

Although double-stranded RNA has been extensively studied in agriculture and significant resources have been allocated to its development over the past two decades, it has not yet fulfilled its commercial promise. RNAi has primarily remained an unfulfilled tool for agriculture, as evidenced by the limited number of commercial seed trait products currently available, which are only effective against one class of insects - beetles. As a result, the vast majority of economically significant crop pests remain unaddressed by this technology.

“RNAi has a problem with the double-stranded RNA trigger. It has some negative characteristics, like breaking down quickly, not being very specific, and having difficulty crossing membranes. The pharmaceutical industry can solve this problem by using a synthetic chemical formulation to change the RNA's surface properties. However, in agriculture, people are moving away from using synthetic chemicals.” Todd Hauser adds, “We need self-assembling molecules made from natural materials that directly overcome the prior limitations of RNA and can be used equally as seed traits or inexpensive topical products”.

Todd adds, “At Trillium Ag, our solution to the primary challenges of RNAi in agriculture is to mimic nature’s mechanisms that use lipid and/or protein interactions for cell-to-cell transport. The problem is that “dsRNA” is not well suited for this. So, we re-invented the RNAi trigger itself, resulting in strong RNAi activation equal to that of the Nobel- winning dsRNA. From there, we added new ‘self-formulation’ features to the RNA so that this same single-stranded RNA further recruits specific proteins and forms a shell-like surface over the RNA - allowing nearly unlimited RNA/protein compositions for stability, targeting, uptake, and modality. This is done without chemicals, as a seed trait or topical, and broadly adaptable to the unmet needs across agriculture.”

Facing a $220 Billion Issue 

Pest-related losses in global crop production are a significant concern for the agriculture industry. According to estimates from the Food and Agriculture Organization (FAO), up to 40 percent of global crop production is lost yearly due to pests. Plant diseases alone cost the global economy over $220 billion annually, while invasive insects cost at least $70 billion yearly. These staggering figures highlight the urgent need for effective pest management strategies and innovative solutions to reduce losses and improve crop yields. “Food security and sustainability will become increasingly critical as the world's population grows. Addressing the pest control challenge will be crucial to achieving these goals,” says Todd

The FAO also predicts that climate change is increasing the mutation of pests and causing certain pests to attack countries that were not used to seeing such infections. The review suggests that pests can establish themselves in new regions as temperatures rise, particularly in cooler Arctic, boreal, temperate, and subtropical regions. A warm winter can assist invasive pests in establishing themselves in new regions, increasing the risk of pest outbreaks and crop damage.

Already, we have seen the devastating impact of climate change on some pests, such as the fall armyworm and Tephritid fruit flies, which have spread to new areas due to warmer temperatures. The review also suggests climate change is likely to cause significant changes in the migratory routes and geographical distribution of pests, such as the desert locust, which is currently the world's most destructive migratory pest. These findings underscore the urgent need for effective pest management strategies and innovative solutions to address the growing threat of pests in a changing climate.

How Can RNAi Work To Combat Naturally The Infection or Pest?

As explained above, researchers can now program the surface of RNA and ultimately take control of stability, targeting, and uptake. “Agrisome is a promising new platform that combines RNA interference (RNAi) and protein-driven activity to target specific agricultural pests with several modalities, overcoming the prior barriers that hindered RNAi. By programming RNA molecules to silence genes in certain pests selectively, Agrisome has the potential to offer a more targeted and environmentally friendly alternative to traditional pest management techniques such as pesticides. This could help reduce crop losses and increase yields, benefiting farmers and improving food security.” commented Todd Hauser, CEO and co-founder of Trillium Ag.

“For example, by silencing genes responsible for the production of gut tissue integrity in a pest while introducing other natural plant defensis, researchers can reduce its ability to feed on the crop and make it harmless to the plant. This precise approach allows for targeted control of pests without harming beneficial organisms or the environment. As such, Agrisome-based pest management strategies hold significant promise for sustainable agriculture, particularly in the context of reducing crop losses and increasing yields.” adds Todd

What Have Been Some Of The Drawbacks Experienced With The Use Of RNAi? 

While RNA interference (RNAi) has many potential applications in agriculture, there have also been some drawbacks and challenges associated with its use. One major issue has been the off-target effects of RNAi, where unintended genes are silenced, leading to unintended consequences. This can result in unexpected changes in the behavior or physiology of the targeted organism, potentially leading to unintended harm or negative environmental impacts. Additionally, RNAi can be unpredictable, as the effect of gene silencing can vary depending on factors such as the specific RNA molecule used, the dose, and the target organism. This variability can make it difficult to predict the outcome of RNAi-based interventions and may require extensive testing and evaluation before use in the field.

Another drawback of RNAi is its potential impact on non-target organisms, including beneficial insects and other wildlife. While RNAi is specific, it is still possible for the RNA molecules to affect unintended organisms in the environment. This can negatively affect biodiversity and ecosystem health and requires careful consideration and evaluation of potential impacts before deploying RNAi-based interventions. However, a recent study by Castellanos et al., 2022 investigated the effects of feeding a parasitoid wasp, Telenomus podisi, with RNA targeting specific genes in its host, the Neotropical brown stink bug Euschistus heros. The results showed that feeding the wasp RNA specific to its genes did not cause harm, while RNA targeting the stink bug's genes was lethal to the stink bug but had no effect on the wasp. RNAi can be highly specific and valuable in integrated pest management strategies.

Finally, RNAi's cost and regulatory requirements can significantly hinder its widespread use in agriculture. The development and testing of RNAi-based products can be expensive, and regulatory requirements for environmental and health impact assessments can be time-consuming and costly. As such, the practicality and feasibility of RNAi-based pest management strategies may be limited by financial and regulatory constraints.

Todd explained that while traditional RNAi is specific, technologies such as Trillium Ag's Agrisome use structural RNAi triggers that offer significant improvements to meet FDA standards and represent a new level of specificity for agriculture. Additionally, the Agrisome platform is produced in bio-manufacturing settings or through genetic seed traits. Although the final cost of goods will vary depending on the product, bio-manufacturing is the most cost-effective and sustainable form of manufacturing.