Changing the way you grow your food via Synthetic Biology

How do we feed 10 billion people by 2050? Sounds simple enough? Produce more food, right? Sadly, it isn’t as straightforward as it seems. Agriculture contributes almost a quarter of global greenhouse gas emissions, uses almost 70% of all freshwater globally, and is one of the largest polluting activities. Simply growing more is unsustainable. Let’s start answering the question by putting things in perspective:

There is ample evidence to suggest that enough food exists for everyone, enough to feed more than 10 billion people. Despite this, hunger still exists. The problem here is not so much about a lack of food production than it is about a lack of efficiency in agri-food systems across the board.

Further, climate change is sending global climatic systems into a state of flux and rapid change. Agriculture is sensitive to shifting weather patterns, droughts, excessive rain and other climatic aberrations, which makes it vulnerable to the effects of climate change.

Systemic inefficiencies in agri-food systems are associated with various parts of the value chain, ranging from agri-inputs to crop development and further final food production. In this article, we will focus on agri-inputs.

Crop production requires inputs in the form of seeds, nutrients and supplements, fertilizers, and pesticides. Currently, most fertilizers and pesticides are produced through an energy-intensive chemical process. Further, synthetic pesticides have a low crop attachment rate, which leads to them being released into the soil and eventually water resources, contaminating them. The contaminated soil and water eventually lead to a drop in the productivity and efficiency of crop production. Apart from this, there are three major shortcomings associated with many current seed varieties:

• Low nutrient-use efficiency, (plants only consume 50–70% of the nitrogen supplied)
• Low tolerance to abiotic stresses like heat, cold, drought, and
• Inadequate quality attributes like nutritional content, appearance, and shelf-life.

The last decade has seen the advent of synthetic biology as a new approach towards improving agricultural systems, with a number of technological innovations addressing issues with and drastically improving current agri-inputs. These technological solutions lead to a more resource-efficient agriculture, while minimizing negative externalities (such as fertilizer run-off) and resulting in a more climate-resilient agricultural value-chain.

What is the synthetic biology approach?

There are over 50 billion microbes in a teaspoon of soil, which interact with our crops in a highly complex manner. Learning about the microbes and their interactions with plants enables us to modify and improve current agricultural methods. Further, genomic studies of the plants we grow give us an improved understanding of the mechanism behind healthy and productive crops. Using advanced techniques in genetic engineering, systems biology and bioengineering, synthetic biology is creating advanced microbial and genetic solutions to improve nutrient-use efficiencies, develop stress-resistant crop varieties and improve the nutrient content and shelf life of crops. While this seemed impossible just a decade ago, synthetic biology has been catalyzed by a major transformation in sequencing technologies and data analysis techniques. DNA sequencing and gene synthesis costs have reduced by more than 100x and faster gene sequencing techniques such as NGS have been developed. This has led to a significant increase in the amount of available genomic data, a gold mine for synthetic biology.

The genomic data availability has led to the development of efficient bio-fertilizers, growth stimulants, targeted biopesticides, advanced crops for insect resistance and low water usage among other traits using a design-build-test-learn cycle. Analogs of these products do currently exist, but synthetic biology-based improvements promise to be more efficient and effective. For example, earlier iterations of bio-stimulants involved generic rhizobial bacteria and mycorrhizal fungi inoculants, but newer versions of these, such as Joyn Bio’s nitrogen fixation microbes, are engineered to have higher efficacy.

Let’s now explore how some of the fundamental synthetic biology techniques are used to develop new agri-inputs and advanced seed varieties.

Many modern crops suffer from low nutrient uptake, tolerance to abiotic stresses, and in some cases, nitrogen fixation which too can be addressed using synthetic biology techniques. For instance, nitrogenases or phytases could be introduced into crops to enable the fixation of essential nutrients, in this case nitrogen and phosphorus. Plants collaborate heavily with microbes in their soils; where such activity is lacking, synthetically engineered microbial colonies in the form of bio-stimulants can be introduced to inoculate the soil and boost the growth of crops and aid in the fixation of essential nutrients. One of the most important plant-microbe interactions is that involving nitrogen-fixing bacteria–there is a major global effort to equip non-leguminous plants with their own symbiotic nitrogen-fixing microbial colonies.

Crops can themselves be engineered​ to release favorable root exudates to manipulate or support microbial activity and improve crop productivities. While photosynthesis is the sole source of metabolic energy for humans, it is an inefficient process. Research is currently under way to modify several key photosynthetic enzymes in the Calvin cycle and the electron transport chain using gene stacking or CRISPR-Cas9. Further, C3 crops such as rice, wheat, canola and cotton, can be modified to be more productive by inducing Crassulacean acid metabolism (CAM) and C4 photosynthesis.

RNA interference is currently being used to develop the next generation of biopesticides. It is used to silence particular genes, which in this case can induce sterility or mortality in insect pests. The application of RNAi-based pesticides can happen in two ways: (a) by genetically modifying plants to express insecticidal dsRNA molecules, and (b) by applying sRNA molecules externally to crops in the field. Another method of controlling insect population is via gene drives, wherein the frequency of deleterious gene types (e.g. those for sterility or lethal genes) is increased.

Fungal diseases are another issue for which synthetic biology solutions exist. Golden Gate cloning leads to one such solution–multiple DNA fragments are assembled, or stacked, into a single piece and provide crops with complex and efficient resistance to fungal diseases.

Big data, too, is playing a crucial role in the field by enabling the analysis of large data sets related to crop genomic sequences, epigenomics and phenotypes. This is then used to engineer novel microbial solutions, as well as predict better seed traits and varieties and thereby speed up crop development and breeding.

A number of companies around the world are taking the technologies we just discussed to commercial markets. Some of them are listed below.

How is the market developing?

Use of biotechnology in agri-inputs has always been met with skepticism by the farmer community. This was also aided by the underperformance of many of the first-generation products. However, bio-based stimulants and pesticides have seen renewed interest over the last decade, especially from the larger players in the market. Bayer bought AgraQuest, a company developing biological pest management solutions based on natural microorganisms in 2012 for $425 million plus milestone payments. BASF followed suit by acquiring Becker Underwood, a company developing biological seed treatment and seed treatment pigments and polymers for $1.02 billion. Similarly, Syngenta purchased Pasteuria Bioscience, which was developing nematode control products based on Pasteuria species for $86 million, plus up to $27 million in deferred payments. The entry of the larger players with brand visibility in the market has also helped improve the sentiments among the farming community regarding these new generation biological products. This has coincided with a large number of startups in the field too, many of which have been started in the last decade.

The sector has also seen interest from venture capital. More than $900 million was invested into agri-inputs startups in 2021 with $430 million in Pivot Bio which has launched its PROVEN 40 OS and RETURN OS, the first microbial nitrogen fertilizers in the market. BioConsortia, which is collaborating with Mosaic to develop N-fixation microbes, has also raised $37 million in private funding. GreenLight Biosciences is developing the world’s first RNA-based pesticides and has received $109 million in funding in 2021. Joyn Bio, a joint venture between Ginkgo Bioworks and Bayer, is developing engineered microbes for nitrogen fixation in corn and wheat fields.

Advanced seed development has generally been dominated by large seed companies such as Syngenta. However, a new breed of startups have emerged who are using data and artificial intelligence along with synthetic biology to speed up the advanced seed development process. Calyxt, which has brought its engineered high-oil content soybean seeds to market in the US, went public on the NYSE in 2017, raising $61 million in the process. Yield10 Biosciences, formerly Metabolix Inc., shifted focus from engineered bioplastics to improved oilseed yields in camelina and went public in 2006, raising $92 million. Cibus, also based in the US, has developed a proprietary Rapid Trait Development System gene-editing platform which is being used to improve the traits of canola. They have raised $131 million to date. Phytoform Labs recently raised $5.7 million for scaling up its AI based genome editing platform.

Synthetic biology in India is in its nascent stages. However, there is immense potential for its use in the agri-food sector in the country. Despite being one of the largest agricultural producers in the world, the country is still struggling to meet the high demand for food. Research is ongoing in several institutes in the country to develop synthetic biology-based solutions for the agri-food sector. Agri-biotech institutions such as NABI, ICAR-IIAB and several others are leading the charge in this direction. Similarly, the startup ecosystem is also making some headways in this direction. String Bio- a company developing biostimulants and alternate proteins through single cell technology recently raised $20 million in Series B funding to commercialize their products. Similarly, BioPrime Agrisolutions raised $1.5 million in 2021 for commercializing their agri-input products. Piatrika Biosystems also raised $1.2 million for developing its AI/ML agri-genomics platform.

Challenges and Opportunities in the next decade:

Apart from a few products that have seen the light of the day, synthetic biology products have a long way to go before they are accepted in the market. These microbial products have a short shelf life (close to a year) and face challenges in their performance due to resistance from the microbial community already present in the soils. There is also a lack of large-scale field trial data to prove the effectiveness of these products. Large scale trials require large capital to be deployed which has been a challenge over the years, especially for startups developing innovative product lines. There are regulatory challenges too, as a majority of countries around the world are still in the process of drafting their policies on synthetic biology technologies.

It remains to be seen if regulation will be able to keep up with the fast pace of synthetic biology innovation. Finally, making these products cost competitive with their chemical equivalents will be key for their acceptance in the market. Luckily, rising synthetic fertilizer prices over the last few years have made the biofertilizer and bio-stimulants markets lucrative.

A number of biological agri-input products are under development which will hit the market in the next decade. Changing consumer preferences towards organic food products free of synthetic pesticides and other harmful chemicals is expected to open a huge opportunity for the biological products. We believe that improving agricultural outputs by using synthetic biology is going to be Green Revolution 2.0. And we can’t wait to see it unfold!

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