7 February 2022
Dr Emma Davies: IBERS, Aberystwyth University.
- Growing pharmaceutical crops could be an innovative way to diversify a farm business.
- As pharmaceutical crops are grown for a specialist end market, identifying the buyer of the pharmaceutical crop before planting is important.
- While yields of pharmaceutical crops are often lower than for traditional farm produce, growing pharmaceutical crops can be profitable if the optimal crop for individual farm conditions is selected.
The bioactive properties of plants have been used as medicinal remedies for thousands of years. Plant derived compounds can have many different properties, including analgesic, antioxidant, antimicrobial, anti-inflammatory, anti-cancer and chemotherapeutic effects. Today, many of the active compounds originally derived from plants are cultivated or synthetically produced for modern pharmaceutical products. Common examples of plant derived compounds include caffeine, aspirin, quinine, quinidine, digitalis, and opium derivatives such as codeine and morphine. Today, research aiming to discover new plant based compounds continues for drug discovery purposes as plants are incredibly chemically diverse. As a result, interest in developing plant-based pharmaceuticals is increasing.
What are pharmaceutical crops and products?
The definition of a pharmaceutical is a substance that, due to the results of clinical trials, is used in the diagnosis, treatment, or prevention of disease. Therefore, pharmaceuticals are medicinal products, and are defined separately from nutraceuticals which are foods (or parts of foods) that aid in the prevention or treatment of disease. Pharmaceutical products are regulated by the Medicines and Healthcare products Regulatory Agency (MHRA), whereas food products associated with ‘general health’ claims are regulated by the Food Standards Agency.
Plants can be termed ‘pharmaceutical crops’, when they are cultivated and used for the extraction or preparation of naturally occurring bioactive pharmaceutical ingredients, used as therapeutic substances in pharmaceutical products. These bioactive substances are often small molecules that are plant secondary metabolites, produced by the plant but not actively involved in normal growth or reproduction. Secondary metabolites can include alkaloids, bibenzyls, phenols, flavonoids, and polysaccharides, amongst others.
In order for a plant derived compound to be used as, or within a pharmaceutical product, it needs to be isolated, purified, and chemically and structurally characterised before being pharmacologically screened and toxicologically evaluated. The compound can then enter clinical trials, where the efficacy and safety of the compound is examined. Once a plant derived compound has been clinically evaluated it needs to be approved for pharmacological use before it can be grown commercially. This process can take many years, however, there are a number of plant derived compounds that have already been approved for use in pharmaceutical products. Many of these plant derived compounds can be chemically synthesised in a laboratory. However, this is often a very expensive, and resource and energy intense process. Growing plants outdoors on a large scale can provide an abundant alternative source of plant derived compounds to the pharmaceutical industry at a significantly reduced cost.
What is involved in growing plants for pharmaceutical products?
As growing plants for pharmaceutical products is a niche sector, the yields expected from these crops is significantly lower than for commercial crops. Nevertheless, pharmaceutical plants can be very profitable. However, to realise their full productive and financial potential, plants used for the extraction of bioactive compounds need to be grown in appropriate conditions and harvested using the appropriate techniques at the most optimal stage of the plant’s life-cycle. The harvest also needs to be stored appropriately before the active compounds can be extracted. Therefore, when selecting the most optimal pharmaceutical crop, any requirement for additional investment into specialised equipment or storage facilities needs to be considered. Additionally, before embarking on the planting of a pharmaceutical crop, growers need to identify a buyer and establish a contract that will specify growing conditions and plant characteristics. Some buyers may also manage compound extraction. Overall, the agronomic benefits, management implications and financial returns associated with a pharmaceutical crop need to be evaluated for each individual farm.
It is also essential that the crop is grown in compliance with legal regulations as some crops are classified as controlled drugs and require additional licensing by the Home Office. For example, low tetrahydrocannabinol (THC) industrial hemp, grown for fibre and oil requires a cultivation licence. While poppies, grown for opium production do not need a cultivation licence, the pharmaceutical companies responsible for processing poppy crops do require a Home Office licence.
Growing pharmaceutical crops
There are a wide range of pharmaceutical crops grown around the world, and in the UK, crops such as daffodils, poppies, borage, echium, and hemp are already grown for commercial pharmaceutical purposes.
Galanthamine is an alkaloid found in the leaves and bulbs of plants within the Amaryllidaceae family. It is one of the most studied alkaloids and is licensed as a pharmaceutical product to treat cognitive decline associated with Alzheimer’s disease in the UK, Europe, and the USA. Commercially, galanthamine is most often produced from daffodils (Narcissus) as they are relatively large in size and produce relatively large amounts of galanthamine compared to other members of the Amaryllidaceae family. As they are also already grown on a significant commercial scale for ornamental flowers, the equipment used for their cultivation is already widely commercially available.
Opium poppies (Papaver somniferum L. and Papaver setigerum D.C) are grown as a source of poppy seeds for the food industry, and as a source of alkaloids, mainly codeine and morphine, for the pharmaceutical industry.
There are also a range of oilseed crops that can be grown for their bioactive compounds in the UK. Oilseed crops often provide valuable sources of different fatty acids that are used in dietary supplements and pharmaceutical products. For example, borage (Borago officinalis) is a high value oilseed crop native to the UK. Its oil is a source of gamma linoleic acid (GLA), used for the treatment of diseases such as multiple sclerosis, diabetes, arthritis and eczema. Similarly, echium (Echium vulgare), is also part of the borage family and is used as a source of GLA. Other oilseed crops with pharmaceutical potential include false flax (Camelina sativa) and safflower (Carthamus tinctorius), amongst others.
The opium poppy is used as a source of alkaloids for the pharmaceutical industry.
Selecting the optimal plant species and plant material is very important as often many different species or cultivars of the same plant have variable levels of bioactive compounds. As a result, a large number of plants and plant materials usually need to be screened in order to determine the most suitable variety. For example, there are around one hundred wild species of daffodil, with thousands more cultivars available, and the amount of galanthamine produced by each species can vary significantly. While narcissus ‘Carlton’ is commonly cited as having high galanthamine levels, one study that examined galanthamine levels in 105 ornamental varieties found that the leaves of Narcissus hispanicus and the leaves and bulbs of cultivars such as ‘Yellow Wings’, ‘Bella Estrella’, and ‘Rijnveld Early Sensation’ also had high levels.
While some plants require arable planting regimes to be productive, growing pharmaceutical plants does not necessarily mean a disruption to established grassland systems. Dual cropping approaches, where plants such as daffodils are grown within established grassland systems which are grazed following harvest, have been successful. Within such systems it has been reported that 80% of daffodil bulbs establish, resulting in successful galanthamine production and maintained livestock performance. This approach would be particularly valuable where permanent land use change would not be beneficial and relatively low yields of pharmaceutical products are required. As some pharmaceutical compounds, such as galanthamine, grown from plants can be extracted from both leaves and bulbs, harvesting the whole plant (including the bulb) is not always necessary, meaning soil disruption can also be avoided. Growing pharmaceutical crops as break crops within arable rotations is also possible, simultaneously providing additional benefits for the farm environment. Using pharmaceutical crops as break crops can provide many valuable benefits such as disturbing the lifecycles of weeds, pests and diseases, improving soil structure, and providing habitat for pollinators.
As with any crop, the concentrations of secondary plant metabolites in field cultivated plants can vary due to geographical location and fluctuate due to seasonal changes. However, the synthesis and accumulation of secondary metabolites in plants can also change in response to environmental stress, including water, temperature, nutrient, and salinity stress. The impacts of these different stressors affect the metabolic pathways responsible for the production of plant secondary metabolites. In many cases, the production of secondary metabolite production increases in response to stress. This is due to a chemical response system which acts to increase the plant’s resistance to the stressor within its environment.
Therefore, some cultivation practices or landscapes characterised by poor growing conditions may be more advantageous for producing some specific plant derived compounds. For example, drought stress increases the production of codeine metabolites in opium poppies (Papaver somniferum), and high salinity, drought or water-logged conditions increase the production of artemisinin, an anti-malarial compound extracted from sweet wormwood (Artemesia annua). The galanthamine content of summer snowflake (Leucojum aestivum L.) can increase by up to four times under high salinity conditions, while the galanthamine content of the spider lily (L. aurea) also increases under mild drought stress during later growth stages. It has also been reported that a variety of plants grown under organic conditions have enhanced micronutrient and secondary metabolite profiles when compared to plants grown using chemical fertilisers. Indeed, many plant species grown for pharmaceutical purposes require minimal nutritive inputs. Examples of food crops whose nutritive and secondary metabolite value increase due to organic cultivation include tomatoes, broccoli, apples and fennel. However, the metabolic pathways of plants are highly complex and determining exact relationships between stressors, stress physiology and secondary metabolite production is challenging.
Transgenic pharmaceutical crops
The term ‘pharmaceutical crop’ is sometimes used to refer to ‘transgenic pharmaceutical crops’. Transgenic pharmaceutical crops are genetically modified using genetic engineering technology to have one or more genes from another species introduced into their genome. Using this method, transgenic plants are used to produce large therapeutic molecules including recombinant proteins such as antibodies, enzymes and vaccines. This process of producing compounds from transgenic crops is referred to as “molecular pharming”.
Transgenic plants used in open field production in the USA include tobacco, rice, potatoes, safflower and cereals. However, transgenic pharmaceutical plants cannot be grown commercially in the UK, and molecules produced using transgenic plants are governed by the same regulations as genetically modified food crops, meaning they require authorisation to enter into the food/feed chain. This largely restricts the use of pharmaceutical products incorporating transgenic plant products in the UK and EU. However, research concerning transgenic pharmaceutical crops is expanding, and the gap between academic research and commercial application may be bridged in the future.
Summary
Plant secondary metabolites are a diverse group of chemicals that are increasingly investigated for their medicinal benefits and use within pharmaceutical products. Cultivating pharmaceutical plants may be a viable option to diversify an agricultural system, however, care must be taken to select the most appropriate pharmaceutical crops for individual farm conditions. As growing plants for the extraction of bioactive compounds is a niche sector, identifying an established supply chain with actors that can conduct compound extraction is very important.
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