Synthetic Biology: Changing the way you eat your food!

TL;DR

• Current food production systems are highly inefficient, both in terms of energy and productivity, and have an adverse impact on our environment.
• Using advanced techniques in genetic engineering, systems biology and precision fermentation, synthetic biology is being used to study and modify the pathways or develop new microbial cell factories for two broad nutrient types: macronutrients such as carbohydrates, fats and proteins and micronutrients such as vitamins, dietary fibers and minerals. These ingredients or nutrients can then be used to produce complex products such as animal meat analogs, alternate dairy products, next generation sweeteners and flavors, functional foods such as carotenoids, vitamins and other oligosaccharides.
• 2021 saw more than $900 million invested into start-ups developing synthetic biology-based food products, a rise of almost 3 times from 2020 and accounting for 60% of the total funding in this sector over the years.
• Although the market in the country for the alternate meat, seafood and dairy industry is small, India has the potential to be a global supplier of high-quality biotechnology-based food products.
• Synthetic biology products are currently being developed at the lab scale and producing these products at an industrial scale will have its own set of challenges. Optimizing the fermentation parameters for high yield, raw material availability, product formulations and stabilities are some of the challenges involved in scaling up precision fermentation to industrial scale.

When Zac Brown wrote this song back in 2005, he would never have imagined a time where his love for chicken would be questioned. But here we are, more than 15 years since he wrote his song, and the world is questioning the sustainability of its meat consumption habit. The quest for sustainable alternatives has powered a revolution in the food industry in the past decade — one in which we are transforming into a more sustainable and environmentally friendly system of food production and consumption.

What is driving this change?

Out of the total calories available from crops grown worldwide, only 55% is directly consumed by humans, while the rest of it is either fed to livestock or converted to industrial products. Large scale agricultural crop production is in itself detrimental to the environment as it involves destruction of forests to convert them into arable land and heavy use of fossil fuel-based agricultural inputs. Much of our food consumption is also indirect, which is inefficient: 100 calories of grain can only be converted into either 40 calories of milk, or 12 calories of chicken, or just 3 calories of beef. Sorry Zac, your chicken isn’t worth its weight!

Notwithstanding the glaring energy conversion inefficiencies, the consumption of meat is expected to keep rising, especially in developing economies such as India and China. Meat consumption and income follow an inverted U-shaped relationship: consumption initially increases with income but eventually reaches a point at which it stagnates or declines. The rising population in these countries as well as the rising income levels, coupled with the calorie conversion inefficiencies, suggests crop production will have to double from current levels to feed the population over the next decade. Arable land, however, is limited. This unsustainable system is driving the shift towards alternative solutions — how do we produce food with minimal environmental impact? How do we improve the efficiencies of meat consumption and produce other types of foods in a lower-impact manner? The answer — SYNTHETIC BIOLOGY.

What is the synthetic biology approach?

What if I told you that we could produce the food we need in large fermenters with very less dependence on farmland? This might have been a distant reality a few years ago, but large-scale food production using precision fermentation systems is slowly becoming a possibility. Fermentation is an age-old technology and several products central to our cultures have been traditionally produced using this technology. Synthetic biology, however, is creating a paradigm shift by enabling the production of complex food products and ingredients, which can be safer, more nutritious, more delicious and more sustainable than currently available ones.

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Using advanced techniques in genetic engineering, systems biology and precision fermentation, synthetic biology is being used to study and modify the pathways or develop new microbial cell factories for two broad nutrient types: macronutrients such as carbohydrates, fats and proteins and micronutrients such as vitamins, dietary fibers and minerals. These ingredients or nutrients can then be used to produce complex products such as animal meat analogs, alternate dairy products, next generation sweeteners and flavors, functional foods such as carotenoids, vitamins and other oligosaccharides.

Alternate Proteins

Proteins are a key component of meat, seafood and dairy products and thus alternate methods to produce these proteins are required to develop animal free products. This is easier said than done- animal proteins from either bovine or chicken or even fish are known as complete proteins, which means they have all the 9 essential amino acids which the human body requires but cannot produce itself. This is true of the proteins present in the meat, eggs and milk from these animals. These proteins have higher digestibility and ability to transport other important nutrients such as calcium and iron in the human body. In addition, these proteins can create gelling, emulsification, and foaming, which gives the food its appealing texture and sensory attributes.

Unfortunately, plant sources of protein such as soy, pea, lentils and others which are currently being used as alternatives to animal proteins have an inferior amino acid composition (eg. low concentration of lysine). These proteins also suffer from slow digestibility issues due to their inherent molecular structure- they are more rigid in nature. This also has a negative impact on the sensory properties of the food products. To overcome these challenges, scientists are using synthetic biology and precision fermentation.

One of the earliest examples of this was the production of hemoglobin- which was found to be useful to provide a meat-like flavor to the plant-based meat products. Researchers modified a strain of P.pastoris by inserting and overexpressing the leghemoglobin gene and the other enzymes involved in the heme synthesis pathway. This led to the production of hemoglobin in high concentrations, making it affordable to be used in plant-based meat products. This process is now being used by Impossible Foods in their plant meat production.

While hemoglobin was produced as a flavor ingredient for the plant-based meat products, new age startups and researchers have now developed technologies to produce microbial proteins which can exactly mimic the animal proteins in their molecular structure, thereby eliminating the need to use plant proteins. Using single cell precision fermentation techniques, they are engineering yeast cells to consume raw materials such as methane and convert it into the desired proteins with digestibility and organoleptic properties similar to traditional animal proteins.

Similar techniques have been applied to develop dairy proteins such as casein and whey as well as egg proteins such as ovalbumin, ovotransferrin, ovomucoid among others. The purified proteins can then be mixed with other components such as fats, vitamins, water to make synthetic milk virtually identical to regular milk. This approach offers significant advantages compared to the traditional dairy farming: low land occupancy, no use of antibiotics/hormones, shorter time for culture development and production and ability to modify the composition to include essential components such as lactoferrin, 𝛽-casein and 𝜅-casein for infant growth and exclude non-essentials such as lactose and other allergens.

Researchers are also developing cultured meat by growing animal cells in large bioreactors. The stem cells obtained from the embryos are differentiated into muscle cells which are then proliferated under optimal growth conditions and nutrient media. The cells are then added to scaffolds or microcarriers to obtain the desired 3D tissue structure. The nutrient media contains serum components which are traditionally extracted from animals. Synthetic biology is being used to produce some of these components including growth factors and hormones such as transferrin, insulin and serum proteins such as albumins.

Carbohydrates

‍Excessive dietary sugar consumption has led to health concerns such as diabetes and obesity. Natural sweeteners with low or zero calories offer an alternative. These sweeteners are essentially carbohydrates such as erythritol, steviol glycosides, mogrosides which can be produced using engineered cell factories in bioreactors. Synthetic biology is being used to develop microbial cells such as yeasts and fungi (S. cerevisiae) with increased productivity and the ability to consume inexpensive raw materials/substrates, thereby reducing the cost of the sweeteners.

On the other hand, Human Milk Oligosaccharides (HMO) such as 2-fucosyllactose and lacto-N-neotetraose provide prebiotic properties. Companies such as Jennewein and Glycom A/S have been able to produce them using precision fermentation techniques in E.Coli and the products have received European market approval as well as FDA ‘Generally Regarded as Safe’ (GRAS) categorization. These products are significantly cheap and are now being used as ingredients in infant products, milk, dietary supplements and medical foods. The learnings from these developments have opened the doors for producing many other oligosaccharides such as hyaluronic acid (HA), hepasoron, xanthan and curdlan which have tremendous opportunities in the food industry.

Fats

Essential Fatty Acids (EFA) such as omega 3 and omega 6 Poly Unsaturated Fatty Acids (PUFA) are obtained from food sources such as meats, eggs and diary products and are critical to the taste of the meat products. Some of these EFAs can also be obtained from vegetable crops such as palm, flaxseed, canola and many others. They are essential to reduce the risk of type-2 diabetes and heart diseases. Synthetic biology is being used to produce these EFAs through precision fermentation techniques, thereby reducing the dependency on animal meat products and large scale oil crop cultivation. These fatty acids can either be commercialized independently or used in plant-based meat products. Yeasts such as Y. lipolytica and Rhodosporidium toruloides are being engineered to produce γ-linoleic acid (GLA), arachidonic acid (ARA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Companies such as C-16 Biosciences, Nourish Ingredients are expected to commercialize these products over the next few years.

Others

‍Flavour compounds such as limonene and vanillin can be produced via engineered microbes to make them cost effective for commercial applications and also to produce them at scale. Currently, these compounds need to be extracted through natural plant sources, and their low natural concentration results in high cost. Engineered cells/microbes can also be used to produce these flavour compounds as part of the food production process. For example, a yeast variant with the ability to produce linalool and geraniol, flavors which are generally obtained from hops during beer production, has been developed.

Traditionally, vitamins are produced via a chemical synthesis route, which is not environmentally friendly and food safety concerns are limiting their usage. This has paved the way for the use of synthetic biology and fermentation to produce these vitamins. Vitamins such as B2 and B12 are already commercially produced using engineered Ashbya gossypii and B. subtilis as well as E. Coli. Research is currently ongoing across the world to develop similar commercially viable processes for all other types of vitamins essential for the human body.

Cellulose is the most widely used dietary fiber and is currently produced naturally by Gluconacetobacter and Komagataeibacter. Cellulose is used as an emulsion stabilizer in ice-creams as well as in creating complex 3D structures in food products. Synthetic biology is being used to increase the cellulose concentrations as well as to improve its structural features to increase the gel strength of food.

How is the market developing?

Investments in synthetic biology-based food production companies has seen an uptick in funding over the last few years. 2021 saw more than $900 million invested into start-ups developing synthetic biology-based food products, a rise of almost 3 times from 2020 and accounting for 60% of the total funding in this sector over the years. 2021 also the first round of growth stage deals in this sector, signaling advancements in the product development and commercialization cycle in the industry. A large part of these investments have happened in the US, followed by Europe and the Asia Pacific region.

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Since 2012, the number of new investors in the synthetic biology market has increased significantly, with more than 40 new investors joining the bandwagon every year, with the total number crossing 400. Today, there are four different types of investors in the synthetic biology food market: accelerators such as Indie.Bio who provide seed stage funding along with lab and co-working space, venture capitals such as SOSV, Big Idea Ventures, CPT Capital, S2G Ventures, Sustainable Food Ventures and many others who provide early-stage risk capital, corporates venture capitals such as Prosus Ventures, Rich Products Ventures and corporates such as JBS, Tyson Foods, Cargill, Nestle and Unilever who have invested in synthetic biology based food companies in the hope of adopting these technologies when they mature and finally crossover investors including hedge funds such as Viking Global Investors as well as real estate investment trusts such as Alexandria Real Estate Equities who are providing growth capital for scale up. This has created an ecosystem for the synthetic biology food companies to develop their products at the lab scale and further scale and commercialize them.

Although the Asia Pacific region has seen lower investments in this sector over the years (close to $150 M since 2018 in alternate protein companies), the market in Singapore is developing into a hub for synthetic biology-based food companies in the region. This is primarily being driven by the Singapore government’s support to bolster local food production along with interest from private equity/venture capital/family offices such as Temasek from Singapore and other Asia Pacific based funds such as Twynam Investments from Australia, Toyo Seikan from Japan among others.

The investments in this sector have largely centered around companies using synthetic biology to produce alternate proteins. In the meat industry, Impossible Foods’ plant-based meat burger uses synthetic biology to produce heme, which gives the burger its beef-like flavour. The company raised $500M in 2021, bringing its total funding to $2 billion. Similarly, Motif FoodWorks has commercialized a yeast-based heme protein which can give the desired flavor and aroma to the plant-based meat products. The company raised its series B round of $226 million in 2021. Companies are also using synthetic biology to produce single cell proteins which can be used to develop alternate meat and seafood products. Calysta has raised more than $200 million to scale up its technology for converting natural gas into single cell proteins. Similarly, String Bio is also producing single cell protein from methane by using synthetic biology and has raised more than $20 million to commercialize its products.

In the dairy industry, Perfect Day has raised more than $700M to commercialize the milk proteins produced through engineered cell factories. Their Brave Robot-brand ice cream is available in supermarkets in the US. Similarly, companies are also producing milk-based products through synthetic biology approaches. For example, Remilk is developing vegan cheese by growing casein in bioreactors and then converting it into cheese. The company has raised more than $130M until date.

The egg industry has also seen synthetic biology based alternative products hit the market. The EVERY Company (formerly Clara Foods) launched its first animal free egg protein in November 2021 by partnering with Pressed Juicery. The company raised its series C round of $175 million in December 2021.

The alternate fats and oils industry has seen precision fermentation-based companies emerge over the last few years. C-16 Biosciences is expected to launch its palm oil food alternative in the next few years and has raised more than $20 million. Nourish Ingredients raised its series A round of $28.6 million in October 2022 to scale up and commercialize its animal-free fats products. Similarly, companies such as Cultivated Biosciences, Yali Bio and Melt&Marble are also using synthetic biology to produce alternate fat products.

The investment trends point to the fact that over the last decade, synthetic biology-based technologies have matured and their application in the development of alternate food nutrients and products are slowly beginning to hit the market. Companies such as Twist Biosciences and Gingko Bioworks are developing technologies to engineer DNA and microbes needed to build synthetic biology products. While the focus has majorly been on alternate proteins, driven by the larger market opportunity in the sustainable meat, seafood, egg and dairy industry and the plethora of genetic information available on protein development, companies are also now looking at developing other nutrients such as fats, flavors (polysaccharides), minerals and vitamins. These nutrients can add value by providing the necessary organoleptic properties to the alternate protein products and be accepted by the consumers. Secondly, high value products such as PUFAs, HMOs, flavor compounds such as vanillin can open up larger markets in nutraceuticals and medical foods, which make these products highly lucrative. With companies raising large amounts of capital, the next decade is expected to see advancements in the scale up and large-scale manufacturing of these products.

The table below gives a summary of the major funding events until date:

The story in India:

The market in India for synthetic biology-based food products is growing at a relatively slower pace compared to the rest of the world. In 2022, MyoWorks became the first cultivated meat company (growing scaffolds and other supporting products) in the country to receive venture capital funding. This was followed by Phyx44, an alternate dairy company developing cell derived alternate milk proteins and formulations receiving private venture capital funding. String Bio, a company developing single cell protein by using synthetic biology approaches is also entering the alternate protein market. The company has raised its Series B round of $20M. Laurus Bio has also developed media components including transferrin, albumins and trypsin for the cultured meat industry through its proprietary precision fermentation technology.

This is just the beginning, as the country offers a variety of opportunities in the sector, owing to several factors: rising population which increases the demand on crop production, highly unsustainable practices in agriculture which includes high use of water and land resources, and availability of research and manufacturing capabilities which can drive the development of advanced biotechnology-led food products. Although the market in the country for the alternate meat, seafood and dairy industry is small, India has the potential to be a global supplier of high-quality biotechnology-based food products. The country is also looking to formulate a national regulatory policy on synthetic biology which will help in streamlining and accelerating the approval of these products.

Future opportunities and challenges:

The decade gone by has opened up numerous opportunities for the use of synthetic biology in disrupting the food sector. Several companies in the sector are in advanced stages of product development and are on the cusp of scaling up and commercialization. Cultured meat and dairy products have already hit the market in some geographies. As more genomic information flows in and newer biochemical pathways are explored, new product lines are expected to emerge as well. However, there are a few challenges that need to be addressed for the products to become widely accepted by the consumers:

• Cost: One of the major challenges with any synthetic biology products is to achieve price parities with their chemical counterparts. After all, would you pay double the normal price for eating chicken grown in the lab? The answer in most cases would be a resounding NO. If the reports from Believer Meats are anything to go by, cultured meat product costs need to reduce further by at least 2–3 times for achieving price parities with the traditional animal meat products. Similarly, Perfect Day’s synthetic biology-based milk product is expected to cost almost twice as much as traditional milk. Certain technical barriers will need to be overcome and economies of scale will have to be unlocked for prices to fall further. There is still debate about the final cost of cultivated meat; while its cost is dropping rapidly, some experts believe that cultured meat will not be a cost-competitive product.
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• Consumer and Regulatory Acceptance: Food products such as alternate meat and dairy need to match the organoleptic properties of their traditional counterparts for them to be accepted by consumers. Since these products are produced using microbial fermentation processes, they also need to be subjected to a rigorous regulatory approval process whereby the products are tested for their safety for human consumption. In a landmark statement released by the United States Food and Drug Administration (FDA), the regulatory body deemed cultivated meat as safe to eat by human beings. Prior to this, Impossible Foods received approval for using their heme product as a color additive in 2019. In 2021, multiple companies including Motif FoodWorks, The EVERY Company and Perfect Day received a no objection letter from FDA on qualifying their products as ‘Generally Recognized as Safe’ or GRAS.
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• Scale up: Synthetic biology products are currently being developed at the lab scale and producing these products at an industrial scale will have its own set of challenges. Scaling up is not simply a matter of using larger fermenters, as their performance doesn’t scale linearly with volume. Optimizing the fermentation parameters for high yield, raw material availability, product formulations and stabilities are some of the other challenges involved in scaling up precision fermentation to industrial scale.
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Conclusion

Food systems are undergoing a significant transformation driven by unsustainable use of land and water resources and rising costs. This transformation is being led by biotechnology-based food products which enable food production in large scale bioreactors, thereby reducing land and water usage, while also enhancing productivities and driving down costs. The next decade is expected to open up opportunities for commercialization of these products, which will require support in the form of financial investments, infrastructure as well as regulatory acceptance. We are ready to taste the next revolution in our food, are you?

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