Probiotics—“live microorganisms which when administered in adequate amounts confer a health benefit on the host”—have been around for years. Microbes genetically engineered to confer health benefits, however, have not.
“The whole microbiome field exploded in human health a few years ago with people looking at using synthetic biology to deliver medicines via microbes, but it never really materialized at scale,” observes Aaron Schacht, CEO at microbiome specialist BiomEdit. “There was a hype cycle, and then people realized it’s not as easy as they thought.”
In animal health, meanwhile, “people have been feeding probiotics to chickens and pigs and cows forever,” he says. “We wanted to bring real science to [understand] why microbial solutions work and use synthetic biology to make them even better.”
AgFunderNews (AFN) caught up with Schacht (AS) to discuss designer probiotics, burping ruminants, and gut barrier integrity.
AFN: Tell us about the origins story of BiomEdit
AS: I was the head of R&D at [animal health company] Elanco from 2015 to 2021 and ultimately after the IPO [separating Elanco from drug company Eli Lily in 2018/2019] and the Bayer acquisition [Elanco acquired Bayer’s animal health division in 2020], it looked like certain areas in R&D would have to be rationalized.
I believed that the microbial biotechnology platform was going to get underfunded and that we probably should find a new home for it. We looked at selling to a strategic, but there was no good option. We looked at private equity, but because there was no revenue stream, that wasn’t an option either. And so the alternative became spinning it out as its own entity and raising venture capital.
By April 2022 we secured a relationship with Ginkgo Bioworks that got us access to their technology platform to complement what we had built ourselves, as well as access to some investors. We then partnered with Anterra Capital to put [$40 million] Series A financing together and launched BiomEdit officially in May 2022.
AFN: What are your capabilities?
AS: While we were part of Elanco, the platform was focused on finding alternatives to antibiotics, which were under siege in the marketplace and by regulators. We took advantage of something Elanco had unique access to, the intestinal or fecal content of thousands of animals, and built a library. From 2016 to 2021, we sampled and analyzed over 10,000 samples from 7,500 pigs, chickens, fish, cows, and dogs.
That was the origin of the sample database that we created, and then we built a platform for culturing these organisms so that we could learn how they grow, and then isolate and purify them. And then we could do genomic analysis, metabolomic analysis, and proteomic analysis to see what molecules they made.
In parallel, we had built a strain engineering, gene editing, and synthetic biology capability, with the idea that we would find microbes of interest that could produce feed additives or serve as a delivery vehicle for a targeted molecule if they colonized the gut of the animal.
AFN: Talk us through how you might approach a given animal health issue.
AS: If you have a leaky gut, it can create systemic exposure to pathogens, so if you can tighten up gut integrity, you can prevent that kind of disease burden or at least reduce or ameliorate it.
And so [to identify probiotics that could be effective], we look at the genomic identity of the bug [microbe]. What gene clusters does it have to make metabolites or biomolecules that play a role in the normal functioning of the gastrointestinal tract?
Does it express molecules that inhibit other pathogens? Does it promote some sort of favorable nutritional cycle by, say, breaking down foods into a short chain fatty acids that are available for biosynthesis by the host?
AFN: And then you could use synthetic biology to do what, exactly?
AS: Several things. One of our products is an enzyme [BE-01], alkaline phosphatase, which degrades the leftover bacterial cell wall remnants from a gram-negative pathogen called lipopolysaccharide, a potent inflammatory stimulant.
In this particular case, instead of using microbes to deliver the enzyme inside the animals, we wanted to use a microbe to express it at scale, isolate the enzyme and then make the enzyme itself a feed additive. In the process, we had to engineer the host strain to get better at producing and secreting the enzyme, so we added extra copies of the enzyme gene into the host organism. So there’s an example of where we used synthetic biology to improve a production host.
Separately, we can use synthetic biology to create products where the [microbial] host is the product and it expresses and secretes the molecule in situ [inside the animal].
So in the case of this enzyme, now we want to put it into a bacterial delivery system because the naturally occurring host that we found is a good production host [to produce the enzyme at industrial scale as a feed additive] but probably not a good delivery vehicle [to express the enzyme] inside the animal.
AFN: Is there a cost advantage if you can get microbes to express the enzymes in situ in the animal?
AS: Absolutely, that’s way cheaper because you don’t have a whole lot of downstream processing. For example, our lead product BE-101 [which protects broiler chickens from necrotic enteritis by attacking toxins produced by Clostridium perfringens], is a pair of microbes that [BiomEdit genetically engineers to] express antibodies to the toxins from C. perfringens.
That just has three steps in the manufacturing process: fermentation, filtration and concentration, and freeze drying.
We spray the product on the back of the birds on the day they hatch, they peck and preen each other, and ingest the product which is a colonizing bacteria, so they don’t need a lot of it.
The colony lasts for about two weeks and expresses the biomolecules that target the toxins. We then give a boost in the drinking water to replenish the colony, which gives us coverage for about five weeks of the growth cycle [The typical broiler growth cycle is six weeks].
AFN: How does this approach differ to, say, using a vaccine used to help control infection?
AS: Typically, the way a vaccine works is that you give an animal an antigen that its immune system recognizes, and it makes its own antibodies. We thought we might be able to offer a complimentary or even competitive strategy by saying, let’s just take colonizing bacteria and [engineer them to] express antibodies that are targeted to specific aspects of the disease biology. Let’s see if we can’t knock down disease activity without requiring the host to generate an immune response.
If an animal is expending energy to fight disease or stress, it’s not producing [growing] at the same level. So is there a way we can give it some tools that don’t cost it any energy? Microbes have their own source of energy for creating antibodies, so if we can install microbes that express biomolecules that affect the disease process, that might be a therapeutic modality that could work. And the good news is, we’ve proven that it does.
AFN: What’s the regulatory status of BE-101, your lead product?
AS: BE-101 is the first product of its kind that the USDA has regulated, so we had to pioneer the concept of a licensing plan for a technology like this. We believe we’ve sufficiently delivered on the efficacy requirements and submitted all the safety studies. We have gotten our master seeds [well-characterized microbial strain] for commercial manufacture approved by the USDA, and those have been transitioned to our contract manufacturer, which is going to scale up to commercial scale for us.
Finally, there is a requirement for a genetically engineered input in the US where we have to get on the Federal Register, a process that entails a risk analysis that we submit to USDA, which further develops a package of information that’s made available for public comment. After that, we’ll do field safety studies in a commercial setting.
AFN: In the best-case scenario, how soon might you be able to get BE-101 on the market?
AS: Q4, 2026
AFN: You’re also working on enteric methane reduction from burping ruminants? What’s your approach?
AS: We got a significant award from the Gates Foundation to look into this. One approach is supplementing the rumen with organisms that are good competitors for hydrogen, but also naturally express molecules that make life difficult for the methanogens [microbes in the rumen that convert hydrogen into methane].
So it was a sort of a one-two punch. Let’s find organisms that can knock down methanogen activity, as well as organisms that are better consumers of hydrogen. Can we come up with a blend of microbes that would shift the phenotype of the rumen from high methane producing to low methane producing?
AFN: How does this compare to existing approaches?
AS: We did not believe we should pursue anything that didn’t confer a productivity benefit [enable the animal to produce more meat or milk on the same rations]. There are a few products that enhance production but do very little on methane, and a few products that knock down methane quite substantially, but do nothing on production.
What we wanted to create is something that did both. For a dairy cow, something that could deliver a 30% methane reduction and a 3% feed efficiency improvement would be best in class.
And maybe we can engineer one of those organisms and enhance the methanogen inhibition to 50%, 60%, or even 70%? And because you’re sparing even more hydrogen, that hydrogen can go to productivity. So could we get 50% methane reduction and 5% feed efficiency?
AFN: What progress have you made so far on this?
AS: Our first consortium of naturally occurring organisms that could have benefits on reducing methane and increasing productivity are coming out of an in vivo study on dairy cows as we speak. And I would say for an engineered variety, starting a study is probably doable by the end of the year as we have the prototype molecules that we know we can engineer in. It’s about picking the right construct now to take into an in vivo setting.
AFN: What is your business model at BiomEdit?
AS: Nutreco, which made a strategic investment in the company in early 2023, has the rights to our feed additive technology, or at least the applications we had in our pipeline at the time [of the deal].
For BE-101, our belief is that for the US market, the broiler industry is so concentrated we can just go directly to the market. For Brazil, our second market, we will probably work with a distributor.
If we get a methane product that can really deliver, however, somebody probably has to buy the company for that, because it’s going to be a significant enough situation where that’s probably the way to access to the full value of the technology.
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