Ag Tech Talk Podcast: Trillium Ag CEO Todd Hauser on How RNAi Technology Can Unlock a New Era of Biological Crop Protection

RNAi was discovered more than 20 years ago and has been used by the pharmaceutical industry to develop a host of novel medicines. Trillium Ag’s research team has found a way to develop biological solutions that target specific pests. In this episode of the Ag Tech Talk podcast, Todd Hauser, Co-Founder & CEO, explains how Trillium Ag uses RNAi technology to unlock a new era of biological crop protection products.

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Podcast Transcript:

AgriBusiness Global: Welcome to Ag Tech Talk, AgriBusiness Global’s podcast exploring the latest technological innovations, tools, and services, that are moving the crop input community forward. I’m your host, Dan Jacobs, senior editor with AgriBusiness Global.

Each episode we talk with industry experts for their insights on ag tech solutions being developed around the world – and how they could impact your business. Whether it’s agricultural technology you’ll find in the field, on a tablet, or in the air, we’ll talk about it here.

Today, we’re talking with Todd Hauser, Co-founder and CEO of Trillium Ag, a biotechnology company that developed a nanotechnology platform that can be used to target specific pests. It gets pretty complicated and there’s lots of science involved. We’ll let Todd explain it. Todd, thanks for being here with us.

Todd Hauser: Well, thank you, Dan, for having me this morning. It’s a pleasure to be here and share TrilliumAg, with you and your listeners and you know Trillium is built on a platform that I’m particularly excited about, because it took us a number of years to scientifically validate this methodology, and TriliumAg is built on a platform that utilizes RNAi, and naturally derived proteins in a combination that I think really mimics what nature provides in terms of natural crop protection methodologies. And we’ve found a way to sort of embrace that, engineer it, and continue on with this use of naturally derived proteins and RNAi to really overcome some of the traditional challenges that we see.

Most importantly, it’s a safe, sustainable technology, but it also addresses some of these really scientific challenges that you see in crop protection things like acquired resistance and being able to even utilize certain modalities. There’s a very exciting modality we all know about RNAi (RNA interference). RNAi has been around, (won the Nobel in 2006 in physiology/medicine) being discovered in 1998. But the methodology that was used to utilize RNAi was based on double-stranded RNA, which is a linear product, and it turns out, had very poor what’s called bioavailability. And so, the development of RNAi was limited because you can eat and ingest RNA, and it doesn’t naturally go into cells, and it’s not something you can use as an active ingredient very well.

Now Pharma was able to get around that and make some very exciting, naturally derived pharmaceutical products. But they use chemistry and excipients and formulation techniques that we don’t have the privilege of using in agriculture, and frankly, nor should we. For us, we were able to, and this goes back to some early days in in my scientific career, reinvent the mechanisms of RNAi with a completely novel trigger.

What I mean by that is, we don’t use dsRNA (double stranded RNA). We don’t use the typical version. We use a structural RNA that allows us to build a scaffolding; and that scaffolding is made of single-strand RNA still elicits the RNA response but allowed us to build nanoparticles in using RNA and plant proteins, and these particles very much like a natural existing particle that might traverse a host cell, we can engineer this protein to deliver our RNA to a target insect very specifically. So, it can work in certain lepidoptera, but not other lepidoptera, for instance, fall army worm versus a butterfly. It can be very specific. It’s very challenging because of the specificity, but it is an exciting space in the sense that it opens up a new forefront on what’s possible for crop protection. So, with this new technology, we’ll be able to start addressing some of these big challenges in insect crop protection without using synthetic chemicals. And so, for us, it’s a very exciting time, as we’ve validated the technology now utilizing it in this in this manner.

ABG: Very interesting. We’ve heard about RNAi, and various other technologies, and I’m sure many of our readers or listeners have heard about it, and probably understand it, but some of them like me — I’m a journalist; I’m not a scientist — So, can you give me a layman’s version of exactly what RNAi is?

TH: Sure. RNAi is an antiviral response that exists in eukaryotic cells. Once RNA has been detected that’s viral, that RNA usually forms a dsRNA intermediate, and that stimulates the immune system of eukaryotic cells.

Plants have it. Insects, part of the animal kingdom have it, and humans. And this this mechanism can be utilized, and what I think Andrew Fire (along with Craig Mello, the pair credited with discovering RNAi) had shown is that when there is a complementarity of the RNA to a target gene it wouldn’t necessarily have to be a viral target gene, it could be by changing the sequence you can use it to target disease-causing genes. And a natural immunological mechanism can be used to target a disease-causing gene or any other gene, and that becomes very intriguing in terms of a mechanism. RNA has a very big and natural origin and a very big potential to it.

And that’s the mechanism we use regardless, even though the RNA is different for tricking that mechanism. But RNAi is part of the natural interval defense system in eukaryotic cells.

ABG: Thank you. You mentioned that pharmaceuticals have used RNAi for a number of years. I think I read on your website that it was hard, or it’s been challenging for RNAi to find a meaningful impact in agriculture. Why has that been a challenge for agriculture?

TH: It’s a multi-faceted challenge. RNAi has limited receptors on certain insects. There’s one class of insects that do respond well to RNAi from oral ingestion, but 85% of the insects that are economically valuable have no response to oral ingested RNA.

And even though they have the mechanisms in their body and the natural immunology to support the use of that mechanism. Getting it from the oral ingestion to the target cells is the challenge, and that challenge is multifaceted, depending on the insect, whether it’s a complicated Lepidopteran challenges like fall army worm. The nucleus and proteases (enzymes that break down proteins). And then you have this alkaline ingestion saliva that is very challenging from a biological standpoint, right? It’s designed to dissolve.

And then, on the opposing side of that you’ve got stink bugs where you have the opposite, you might have nucleuses and proteases, but it’s acidic, and so you get precipitation. So, biologicals are challenging, and nature uses biological for its ongoing war between plants and insects, and insects adapt and change their digestive composure to defend against the plants’ defenses. So, we’re playing in that space.

We just found a way to engineer it and outpace the insect’s ability to adapt. So, we use these natural mechanisms, these natural methodologies of use of protein and RNA to overcome those barriers it had already evolved to avoid, and we take advantage of that that speed of which we can deliver a new composition to that insect that it’s never seen.

Let me give you an example. We might take a certain corn or a couple corn proteins and wrap them on the RNA in a way that is not typically experienced by the insect. So, even though they’re natural protein that it’s used to kind of ingesting one-by-one, when they’re in an aggregate on a nanoparticle, it sort of changes the activity level of that protein. We sort of accentuate the effect, and then we add a couple of other components, a couple of other proteins that help get the RNA into their gut cells in a natural way that can get to stimulate the RNAi effect. And it wouldn’t have been possible, if we were using the canonical long dsRNA, because when there’s a challenge of availability like we have with this, there’s a window under 200 nanometers, a physical size, that a particle has to be linear. dsRNA, If you make it longer and you start formulating, you get big globs that matter that they’re larger than that that window of a by viability so, it was unusable. For us, building a scaffold that we can control is maybe a 50-nanometer diameter, and it’s finite. It’s programmed. It’s locked in when you code it with the proteins, it’s 100 nanometers, and it offers a very precise, almost pharmaceutical level of product for agricultural use. And all of these processes that we’ve designed and developed are self-forming.

It can happen in a cell-free system, or it can happen in plants just like it does in nature. And so, we really engineered this to take advantage of a lot of features that make this possible and make it sustainable.

We can’t add formulation. We can’t add downstream excipients and expensive purification processes. So, we have a self-forming process that assembles our product made from mostly plant proteins that we utilize and then RNA. We make everything here in a cell-free, plant-derived system.

So, we experiment with different systems, or even experimenting with the use of weeds for the production of our bi0reactors, so that we can make products in essentially weed material.

And that’s important that it’s a naturally derived system, and it wouldn’t have been possible if we used the traditional RNAi. So, it was very exciting for us to develop this system over the years. I wish I could say we were years ago looking forward, and this is what we’re going to solve. But it actually was serendipitous the way everything happened, the trigger being fully different than the Nobel winning system. The nanoparticles that are self-forming. We designed the system originally for biopharmaceuticals, and there is a massive convergence going on between the farmer space and the ag space. And the two are coming together in the sense that you can manufacture interesting biological medicines and interesting bio-agricultural products in planta and in plant derive cell free systems.

And that’s an exciting bigger trend or a bigger occurrence than what I’m talking about here today. But we’re in the right space at the right time.

ABG: I guess I have asked this earlier. How is this actually delivered? How does how does it end up getting to those target pests?

TH: That’s a great question. So, for the most part, the products that we are developing are orally derived. There are possibilities that we’d have products that are more topical that go through different parts of the host insect. But for us in our early-stage product development we are focused on orally derived products. Now, this technology, as you can imagine, isn’t limited to insect crop protection. We are also focusing on plant-based crop protection and removing synthetic chemicals from the herbicidal space.

That, of course, is a topical application that goes to the model and into the into the plan sales. But the most interesting thing with the technology is, the platform supports variations so we can coat the nanoparticle with different proteins, and there’s a kind of a golden rule in science that the surface of a nanoparticle determines its overall destination.

I’ll give you a natural analogy in the world of single-stranded RNAi viruses that infect insects and plants by the tens of thousands, there are many different types of capsid surfaces, and those capsid surfaces are naturally derived, and they are selected for optimal penetration of certain plants or certain insects, and that’s called tropism. And the RNA on the inside of those capsids can be totally different, and have a different function that the capsid on the outside. So, by controlling the surface of that capsid nature delivers those viruses, some of them symbiotic, some of them pesticidal to different organisms.

And that’s that tropism effect is all dictated by the surface of the nanoparticles, so that golden rule applies to us as well. We just found a way to engineer it without being viral, without being infectious that we can take advantage and structure the surface of our nanoparticles so that they have the features that are required for lepidoptera, hemiptera, coleoptera.

And whether it’s topical or it’s implant or biological topical, or to target certain weed paths in the field as an herbicide. So, I’m excited about where this is going, going forward, and it really goes towards solving how to bring RNAi modalities into agriculture; how to use these natural mechanisms effectively without adding costs, without adding chemical excipients and making a sustainable food security system for all, since really what we’re all about here.

ABG: You mentioned the term you used with scaffolding is that the agrisome?

TH: Yeah. So, I guess there’s a lot of words we use to describe it. But the RNAi on the inside is an interesting piece of RNA, because it’s a single-strand RNA that has all sorts of interesting structural features, so it forms on itself kind of like an origami or scaffolding, so it builds a spherelike structure, and that spherelike structure has all sorts of little arms. At the same time, it is the active ingredient. The RNA has complementarity to the target genes at a very specific pharmaceutical level of specificity and holds the structure at the same time acts as an assembly scaffolding for the agrisome.

The agrisome is built on that RNA that forms it builds a structure. It has little arms that stick off outside of that sphere that collect a protein.

In a milieu of a slurry, we can co-express a corn protein and RNA and maybe three or four different proteins, and we for the first time can control the surface of the nanoparticle – sort of like a geography of nanoparticles. Even those are 50 nanometers we’re controlling which protein goes where and how many proteins go on the surface of the nanoparticle. Now, that fundamentally is a new capability, and (we’ve) been doing this for a long time. Traditionally, in scientific formulation, you’re mixing positively charged things with negatively charged things and sort of mixing up a concrete in a buffer and hoping your concrete is appropriately sized, and you’re trying to alter your buffers and your excipient, so you can get that structure.

For us, we don’t have to do that. The scaffolding controls that structure, and it’s self-assembling and so it’s a neat capability. We look at this. We test it in fluorescence, looking at green fluorescent protein … watching them assemble and form these particles. It’s really a phenomenal thing and I think we’re really at this new capability is going to open all sorts of opportunities and uses in the field of agriculture and biopharmaceuticals, but it’s a cool thing to see.

ABG: Sure. We’ve heard a lot about genetically modified crops. We’ve heard Crispr you know you know technology that the lay person seems to be a bit afraid of. Is there a concern that when you start talking about technology and putting things on seeds, or into plants, into crops that people might just kind of freak out about this or is this not sort of in that same world.

TH: Well, I think that the important thing is when I look at the food security problem, and I think about sustainability, and I think about what the threats are, I think about synthetic chemistries as my first, my first de-risking part. Anything we can do to get rid of synthetic chemicals is important, but also being cognizant of people’s concerns on GMOs.

There’s a couple of different aspects to this company that make it sort of unique. The products that we built are plant derived. They don’t have to be a GMO. We make plant cell-free systems that are making naturally direct products that we spray on topically has nothing to do with the genetics of a plant or making a heritable change to any organism. But that being said, the use of GMOs and putting this product, this sort of technique into a plant could be very useful for protecting crops. It doesn’t have to be food crops but for utilizing natural mechanisms that already exist in the plant taking advantage of those, and in sort of emboldening them against their natural pests. Now, when we talk about mechanisms and insects, these are natural mechanisms. We’re not adding anything, and anything we add to the plant is not going to be heritable in a negative way. We’re taking advantage of the proteins. It’s already making in a way. So, it’s not something we’re not adding proteins to the plant, and if we add RNA, there’s you know the RNA that’s in a plant is unquestionable. It’s ubiquitous. RNA is part of nature. By itself it’s benign. It has to be.

It has to have purpose. It has to be designed very specifically, and it’s very challenging, and I would say the risk, even looking back on traditional GMOs, the risk is questionable. I mean, there were a lot of early-day fears on ‘if you eat this product that has different, RNA in it, it was going to make you like Frankenstein, or whatever. It never happens. You ingest RNA with everything you eat, every piece of natural food that we eat is filled with RNA. So, it’s not necessarily something that is going to affect you, but it is a concern I understand amongst the public.

So, for that where there is question, we have topical products that are biologically derived that are useful. Industries where they don’t allow GMOs we’ll use topicals, but where GMO is possible in the sense of food security, cost, and safety, it has a lot of interesting attributes that can’t be ignored. And we owe a lot actually to like the early days of Monsanto and what they had done in the industry. They put a lot of resources towards validating the technique, the safety of the techniques, studying the safety of it with EPA over many years now, and so far, with all the regulatory bodies, we can all rest assured that whatever goes to market is safe.

To me that’s more important. That’s the most important thing that we can do. And that’s why we’re in this in this space. But really the real threat is synthetic chemistry. That’s the real issue that is scientifically valid in terms of its risk to human health, right? And so that’s where we’re at so, but we do address both markets.

ABG: Speaking of synthetic, is this something you see down the road, whether it’s two years, 10 years, 30 years from now replacing synthetic chemistry. Is that where we have ultimately headed? Is that the goal?

TH: That’s the goal. Synthetics have a leg up because of the potency. What makes them effective also is what makes them dangerous. They’re small enough to traverse a cell membrane, and so they can get into all sorts of off target-cells. And that’s what makes them so good, so potent.

For us, the challenges within the barriers of biologicals, making our biologicals potent enough to compete with synthetic potency and then have all the benefits of sustainability and safety on the biological side. And so, I do believe that we will solve this, and not just me. But there’s a lot of brilliant people in the industry working on the problem. They have all sorts of solutions that they’ve come up with. We’re just part of this process is going on, right? I’m very positive that this is the likely outcome, and there’s a lot of resources being put into making it. Everybody wants food security, and everybody wants safe food. It’s interesting to watch the media over a number of years, decades even, and also having known these executives and scientists at large, multinational agricultural companies. These guys are working day in and day out to make food safe and affordable.

And they are doing some amazing work. Yes, there’s been lessons learned from 25 years ago, 15 years ago. But where this industry is going now, if you look at where Corteva is going, and I can’t speak for any of these companies. But from my view it definitely looks like biologicals, naturally direct products is a big emphasis on their product pipeline going forward. And so that’s fitting with Trillium. Trillium is all about that as well. There’s a nice convergence in several areas that I mentioned earlier, and there are reasons for optimism for growers, a farmer, even as a consumer and that your food will be safe.

ABG: Sure. Technology often outpaces the regulatory environment. We’re looking at things like Chat GPT. The artificial intelligence stuff that we’re hearing a lot about, right now. Where does this fit into the regulatory environment. I know different countries have different approaches.

TH: Right. And different compositions have different regulatory implications. For instance, as you mentioned, if we make a trait-based product I think you, to it as GMO that has a different regulatory life cycle than does a topical, and the topicals are much shorter, and it’s easier to get to market, because you simply show that it’s made and something doesn’t spread disease, and it’s made naturally to right proteins, and typically most things we make are made for products that are what are called GRAS (generally regarded as safe).

And so, the regulatory hurdles on the topicals are much lower. That being said, there’s greenhouse trials, there’s a lot of safety studies that go into anything just to make sure you don’t miss something right, even if it’s not required by the regulatory body. Everything is studied.

We do have to comply with our regulatory systems, and we fit right in. Trillium, we haven’t talked about this, but Trillium is probably not a company you’re going to see a product from in the near future. You’re likely to see our technology inside existing products from larger companies that have the distribution and the regulatory scale to handle and to support that the regulatory process. Trillium is more of a technology provider kind of like an “Intel Inside” sort of capability. But that being said, we’re not against developing going through the regulatory process with the product to take it to market. And there’s a lot of exciting opportunities that this technology, I think, will bring especially some new product categories that that might have more or less easier process to market simply because of the natural nature of our product development.

ABG: You led right into my next question, which is where are you in the development phase? And how soon might we see something that uses this technology available to growers?

TH: As I mentioned in the early part of our call is the technology has been under development for a number of years, and Trillium was sort of in stealth mode for six years, validating the RNA, the assembly, the protein that I’ve got the basically the agrisome platform. So, we’re an inflection point, a turning point where we just moved from technology development into product composition development. And so, this is an exciting time for us, because now the rubber hits the road; we have in our pipeline, a product for fall army worm, for stink bugs for acquired resistance coleoptera and we’re developing these products. And I’d say we’re a year away from field trial.

And so, once we get to that, then it depends on the partners and regulatory processes how soon you’ll see it. It’s still a number of years away.

ABG: You mentioned a few of the targets you have right now the fall army worm, the stink bug. I think Palmer amaranth was on your website as well. Is it about the biology of a given pest? This sort of works better for them, or you can at least target specific cells in those pests. Is it going to ultimately become something that can be used for on any pest, hopefully, or at least many more pests.

TH: Thank you for highlighting that question. The answer to that is the reason we chose our pipeline targets. Fall army worm, stink bug, and acquired resistance coleoptera is the challenges that are intrinsic in each one of these insects represents failure points in the traditional RNAi industry, so they couldn’t target coleoptera. They’re ineffective against fall army worm, and they the only Monsanto product to make it to market led to a quick acquired resistance in Western corn rootworm. The reason we targeted those three is to demonstrate the capabilities of this platform, that highlight its features over the past failures.

It by no means limits what we’ll be able to do with the technology. Yes, we would target eventually, all economically valid pests, whether they’re viral, fungal, insect, and plant with the same technology. We’re just demonstrating with, without coming out of the gate withproducts that are designed to demonstrate the efficacy where everyone else has failed would be a great way to start. Now that being said, fall army worm was also chosen because it’s a $37 billion problem.

It is a national emergency on two continents, and it’s an insect that is and a and represents a class of insects that cause significant damage to crops. And so, there’s economic drivers for that, as well as scientific demonstration.

ABG: Sure, this has been really fascinating. What’s the best way to reach you?

TH: Yeah, they can email [email protected], and that is also on the website, and they can ping us, and then we’ll open up a direct dialogue with one of our team members from there.

ABG: And just so people know Trillium is T. R. I. L. L. I. U. M. And it’s Trillium Ag, right? I appreciate your time.

Today we’ve been talking with Todd Hauser, co-founder, and CEO of Trillium Ag who have developed or working on developing RNAi solutions to treat specific pests. Any last thoughts?

TH: Thank you very much for having me today. If there is another opportunity to come back and see you again as we get close to product release. I would love to do so.