Bioactives: What are they, why are they important and how will they impact CEA and Ag-tech?

With phytonutrients trending, we want to delve into what we mean by ‘bioactives’ and how they could impact Controlled Environment Agriculture (CEA). Put simply, bioactives are physiologically-active compounds located in plant organelles with the potential to positively impact human health. Studies indicate that consumption of a diet rich in bioactive compounds with antioxidant activity, including vitamins, phytochemicals and phenolics such as flavonoids and carotenoids, can diminish the risks associated with diseases such as cancer, heart disease, diabetes and other age-related degenerative conditions.

The ‘crunch’ question: is extracting Lycopene as a drug more beneficial to our health than if we eat tomatoes as part of a healthy diet? The answer?  It’s all to do with health status, efficacy and balance.

Why bioactives could be a good investment 

Bioactives have already caught the attention of investors, eager to tap into start-up companies with million-dollar investments which could  elevate them from their niche status to fill emerging gaps in healthcare, and in the process help CEA farmers gain from a move to: 

• grow the best quality functional plants in a controlled environment.
• recreate environmental growing conditions in any geographical location.
• breed new genetics leading to nutraceuticals stable enough to improve human health. 
• increase the level/production of selective bioactive metabolites. 
• widen the market opportunities to sell more diverse fresh fruit and vegetables using CEA.

The evolving challenge of drug resistance, and the need for novel drugs to treat diseases like cancer and Alzheimer’s has led to an increased demand for new bioactives worldwide. Even before the pandemic struck, healthy foods and supplements fortified with plant extracts were on trend. A report in January of this year also indicates the health and wellness sector is gathering momentum, with the global market for bioactive ingredients expected to reach 317 billion USD by 2030. More than a quarter of this market will come from functional plants.

Can CEA play a role in amplifying bioactives in functional  plants?

CEA could accelerate the early stages of drug discovery, harnessing the power of controlled environments to deliberately stress/elicit plant responses to produce higher yields of bioactive molecules. Plant bioactives provide a natural protective role against biotic and abiotic stress. Plants that are free from disease can easily be studied in a controlled environment, preparing them for either uniform extraction or controlled genetics: the protected environment easily permits monitoring and maintenance without introducing any unwanted genetic variation. By transitioning plants towards ‘survival mode’ it pushes the equilibrium in favor of more efficacious specialized bioactives. 

Bioactive exploration is complex but it does not mean farmers can’t grasp the methodologies and their importance 

Metabolic pathways are complex: they produce multiple modified bioactive intermediates which make them difficult to define. Finding new ways to identify important bioactive compounds requires an inter-disciplinary approach. Metabolomics and computer-aided drug design (CADD) have emerged as the strongest fields in plant drug discovery which accelerates the selection of efficacious molecules compared to traditional pharmacological techniques. This advance is attributed to new technologies making it possible to study the plant metabolome using advanced technologies to screen and analyze the effects of bioactive molecules faster than ever before.

Let’s take a quick run through some of the production methods used to scale up important bioactives

• Precision fermentation using microbes has been popular in recent years but has for decades been used to scale up bioactives. Genetically engineered yeasts, algae and bacteria have all been used to cultivate bioactives. 

• Protoplast culture is another efficient method where the outer protective plant cell wall is enzymatically removed and the cells become ‘totipotent’ with the ability to differentiate into any cell type. These uniform cellular suspensions can then be used to manufacture high-value specialized metabolites. 

• Hairy root culture has also been used as a scaling method for many years to allow bioactives found specifically in plant roots to be extracted. Thanks to our friend in Indonesia,  Dannis Kusuma we can share his adventitial culture of Gynura procumbans (sometimes called longevity spinach for its extensive health properties) in bespoke bubble reactors used to extract specialized metabolites from the roots. Click the image to see more.

• Molecular farming uses novel DNA inserted into an Agrobacterium which is then mechanically loaded into the plant, using a syringe on the leaf underside. Nicotiana benthamina, a close relative of  Tobacco, is often used as the vector due to its fast-growing nature and ability to be genetically transformed with good efficiency. This drives the plant to express desired bioactives in plant ‘biofactories’ including antibodies, hormones and vaccines. 

New bioactives are processed downstream; whether they are produced in microbes, protoplasts or are agrobacterium-mediated, production will follow relatively similar methodologies. Regardless of the intermediate, extraction and purification are likely to follow a similar enrichment pathway.

Vanilla – CEA innovators are growing this valuable crop but it could also help identify novel bioactives 

The subtropical ingredient we all love to flavor our ice cream, Vanilla, comes from the Orchid family; Vanilla Planifolia (commonly known as Bourbon Vanilla), is a native of Mexico that requires a high-humidity environment to grow successfully. 

What bioactives are present in Vanilla?

Vanillin, a phenolic aldehyde, is one of the main bioactives derived from vanilla and is the second most used natural flavor in the world. It demonstrates diverse bioactivity, including anticancer, neuroprotective, and antibiotic properties. Currently, 95% of vanillin is produced by chemical synthesis of lignin and guaiacol. Manufacturing vanillin using petrochemicals or by precision fermentation, either microbial or yeast based, has many limitations, not least that such methods cannot recreate that wonderful vanilla flavor you get from natural seed pods in what is a complex process with high energy consumption. This has led to renewed interest in low cost bio-based alternatives. 

But one of the problems in scaling up natural vanillin is that production is a long way from its market. Of the locations around the world suitable for growing the orchid, Madagascar in the Indian Ocean is probably the most well-known, producing around three thousand tons per annum. 

The issue with natural production is apparent

Vanilla production is labor-intensive. It can take up to 600 hand-pollinated blossoms to produce 1 kg of cured vanilla beans. Beans are picked while still green and sold to fermentation plants, where workers sort, steam and dry out the beans in the sun. 

Vanilla is also subject to market fluctuations : recently oversupply has resulted in a crash in prices. This has led to stockpiling of cured vanilla, resulting in a handful of investors driving down the price of ‘green’ vanilla for growers. When tropical storms batter growing regions, the price of cured vanilla fluctuates, creating profits for the investors but leaving farmers at a loss. This is an unsustainable cycle which leaves farms at the mercy of unstable markets, climate change and crop theft. Also, when stored for long periods in a warehouse, it is not in the best state to provide bioactive molecules, so we need to investigate different production routes for the end market.

Growing Vanilla in hydroponics 

We believe CEA could provide a solution, giving the opportunity to produce locally-grown vanilla which circumvents market fluctuations and storage issues. Despite limitations, researchers in Holland are pushing the boundaries in CEA, resulting in secure local production: Dutch growers are presently leading with greenhouse grown vanilla cultivars. 

The rise of synthetic biology versus CEA – they should ideally operate side by side to bridge gaps in preventative medicine in addition to food production and pharmaceuticals. 

Given the limitations in the latter methods, an opportunity could present itself for Agritech companies to exploit more efficient ways to produce vanillin. This includes protoplast scale-up and stem cell precision techniques to provide increased biodiversity for extraction of the full vanilla entourage effect, whereby many compounds in the plant work together to magnify the effect. 

Health care of the future includes a viable role for CEA

Many bioactives known to improve human health have already been extracted from well known plants including  Turmeric, Aloe Vera, Vanilla, Saffron, Ginseng, Ashwagandha and Echinacea, to name a few. All of these have been successfully grown in CEA so who knows the possibilities. Others, like Wasabi, are awaiting discovery to literally enjoy their day in the sun or under LED lamps.

With new ways to quantify the plant metabolome and predict physiological changes in human health, the field of metabolomics is opening up efficient ways to study changes in the class and contents of metabolites in different parts of the same plant, and at different levels of plant maturation. Control of growth is going to be a key factor.

We know the type and concentration of bioactives produced by a plant are influenced by a multitude of environmental factors. The most relevant are light, airflow, temperature, humidity, water, CO₂, dissolved oxygen, nutrients, and substrate characteristics.

All these aspects variably affect the quality and quantity of specialized metabolites, limiting extensive exploitation until a high level of process standardization is achieved. Improving the productivity of functional plants will require innovative solutions that increase yields in both greenhouse and indoor farming. Implementing cultivation in controlled conditions is a potential solution for ensuring the best growing conditions, where not only all the variables can be held for the optimal growing conditions, but also the plant metabolism can be forced and stressed to stimulate the biosynthesis of valuable compounds.

Let’s return to the original question: should we extract bioactives to develop clinical drugs?

Preventative medicine is always going to take the form of a healthy diet and lifestyle (i.e. tomatoes) whereas reactive healthcare is likely to benefit more from purified bioactive molecules (i.e. Lycopene). The CEA industry has many advantages over traditional breeding programs which position growers at the forefront of unlocking the power of plants to amplify the amount of the compound for drug development. 

Through recent turbulent times in the industry, it has become clear CEA farms will need to adapt. According to the investment sector, farms of the future are likely to include the following characteristics:

• Differentiated genetics enabling higher yields and/or broad produce varieties
• Industrial automation which, when combined with biotechnology, drives positive product unit 
• economics.

Farmers in a Venture with scientists – Is that a big Chris Higgins horti beard we spy?

Where farmers are proactive – in that their healthy produce prevents disease – scientists are more reactive: their products treat disease, tackling health problems from a different angle. Despite the difference in approach, there’s no doubt scientists could benefit from partnerships with CEA farmers and breeders to provide clean plant material.  Uniformity is likely to be a main driver in the discovery of these bioactives, and CEA farmers are in a perfect position to drive it forward. Both can collaborate with technology providers to create the right environment to produce sustainable bioactives. 

Unless otherwise stated, all images are from The Functional Plant Co and property of Urban Ag News.  Our experts, Dr Janet Colston and Dr Shashank Saini are available to answer any questions you may have on bioactive exploration. 

Janet Colston PhD is pharmacologist with an interest in growing ‘functional’ foods that have additional phytonutrients and display medicinal qualities that are beneficial to human health. She grows these using a range of techniques including plant tissue micropropagation and controlled environmental agriculture to ensure the highest quality control.