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From Consortia to Recombinants: opportunities and challenges facing the next generation of microbials

In this blog post I will discuss two themes that I see driving the next generation of live microbe biologicals for agriculture. These are the rational design and delivery of pairs or consortia (which I will define as more than two microbes) and the commercialization of engineered strains.

Biotech meets Biologicals – engineering microbial traits

The only commercially available engineered microbial product is Poncho/Votivo 2.0 from BASF, which expresses an endoglucanase on the spore to release sugars from the soil thereby stimulating microbial growth. Several companies are looking to change this. Leading the way are Pivot Biosciences with JoynBio hot on their heels.

Significantly, both are targeting Nitrogen availability. The need is clear from a Grower and sustainability perspective, the phenotype is easy to screen in the lab and it is much easier to design a field trial looking for efficacy against a specific abiotic stress rather than generic “yield”.

The ideal recombinant biological would start with a host strain or “chassis” that is native to the crop target. This is certainly Pivot’s approach, starting as they are with a known corn endophyte and Joyn are leaning heavily on the Bayer microbial archive as a starting point.

The actual engineering approaches are a bit of a black box. JoynBio will be leveraging Gingko’s foundry and presumably therefore going fully synthetic from a native chassis. Whether Pivot are choosing to edit or go with a cisgenic or transgenic approach is not clear. As discussed below this will have Regulatory implications, particularly in Europe. At least we know Pivot’s approach is three-pronged: Decouple nitrogenase biosynthesis from nitrogen sensing, limit assimilation of newly fixed nitrogen and abolish reuptake of secreted ammonium.

Challenges for GMO Microbials

Both JoynBio and Pivot Bio are obviously conscious of the regulatory and consumer acceptance implications of their engineering approach. Both claim to be pursuing a non-GMO approach through editing or random mutagenesis even if, as in the case with the JoynBio, proof of concept is established with traditional engineering approaches. The regulation of these products and consumer sentiment are a moving playing field globally and a tip-toe approach is warranted. I do think avoiding transgene insertion will create a ceiling for application, particularly when it comes to adding modes of action to the same chassis.

Is it better to engineer or discover? A concern with engineering is that the enhancement of one trait will lead to an overall fitness cost leading to other native strains out-competing it in the soil environment. However, starting with the best Nitrogen fixer in a diverse soil-derived archive and improving it by engineering rather than dirt-digging and screening, on the face of it at least seems more efficient.

Consortia 2.0 – letting biology decide

Whilst consortia products do already exist on the market, their constituents are derived by simply testing various combinations of beneficial single strains to find the most efficacious combination. In other cases, it has been by the deliberate combination of strains with modes of action complementary towards the overall purpose of the product. More recent efforts let biology do the designing – looking for interactions in a microbial community to drive strain selection.

Two companies I see leading the way here are Bioconsortia and my own employer: Boost Biomes. Bioconsortia’s Advanced Microbial Selection platform has led to the discovery of individual plant growth promoting microbes, but also enables analysis of the root microbiome as a whole, in particular, interactions between microbes. Co-occurrence of strains suggests synergy and therefore potential strain combinations likely to support the growth of the microbe driving the plant phenotypic response.

Whilst this method does identify interactions in a real biological setting, it does suffer from a shortage of the replicates needed to gain statistical confidence that an interaction is real. The Boost Biomes approach avoids this issue. Here, microbiomes are split into 3000 sub-populations and grown in several different media or environmental pressures. Next generation sequencing of each sub-population reveals that some species co-occur in the same well more often than random, indicating synergy. The pairs or consortia of interest are subsequently isolated and screened for a phenotype of interest. Whilst the in vitro nature of this platform does allow for high repetition, it is far removed from the native environment of a plant. Boost mitigates this by only considering interactions that are maintained across all growth conditions as being those likely to be real.

It remains to be seen whether these microbiome-based (and in my opinion more elegant) approaches to consortia design will produce better products. “Better” here in theory means more consistent performance across a variety of soil types and environments. By being deployed with a sycophantic entourage, the active microbe is more likely to be resilient under stress.

Co-fermentation and Registration – the challenges for consortia

What of the challenges associated with deploying multiple strains? The obvious one is production at scale. Ideally you co-ferment your strains and the resulting ratios are stable, consistent and efficacious. As the number of strains increases though this gets less and less likely. Though it must be noted that Agrinos has achieved impressive success co-fermenting 22-strain consortia designed based on mode of action. The interaction-based approach at has the advantage of grouping strains based on known synergies, which should mean they play nice in the fermentation tank.

The other issue is registration of biocontrol products. Currently there are no consortia registered for biocontrol, so this will be a learning exercise for the EPA. The dilemma is whether companies will be required to register each strain separately rather than as a single active. Common sense would suggest the latter. After all, the end-product is what gets consumed and separate registrations will mean the cost (around $500k per strain) will soon limit consortia size. On the other hand, registering each separately may streamline 2.0 products with different strain ratios as you will merely be recombining registered strains. Clarity is needed from the EPA on this if the potential of these products is to be realized.

To conclude, I am seeing that the more mature microbials companies are winding down their de novo discovery efforts and are moving towards leveraging existing archives by combinatorial screening or genetic modification. The potential for these next generation microbials is clear. For this to be realized, the regulators must share this vision and see that the benefit to growers, consumers and the environment outweigh the need for additional registration burdens.

James Pearce is CSO at Boost Biomes. James previously held positions at Syngenta, Cibus and Monsanto, and is now thoroughly enjoying the challenges of building an early stage biotech company. 

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