Take home messages:
- There are many plants which can be used in the production of pharmaceutical products, and vertical farming could be useful in their cultivation by providing a consistent, controlled growing environment.
- Some plants produce controlled substances and GM crops face legal restrictions, though the contained environment of vertical farming could be useful in preventing GM crop contamination.
- Though pharmaceutical compounds are sold at high prices, expenses associated with extraction and purification necessitate modelling and experimentation to maximise yield before engaging in full-scale production.
Biopharmaceuticals refer to pharmaceutical products which are made, at least in part, using biological processes in living cells, as opposed to being produced chemically using synthetic processes. The biopharmaceutical industry is extremely large, being valued at US $437.12 billion in 2022 by one estimate. Currently, most biopharmaceuticals are produced using yeast, bacteria and mammalian cells. However, yeast and bacteria cannot create some of the compounds required for pharmaceuticals such as the addition of human-like post translational modifications (PTMs). As such, mammalian cells are the most common method of biopharmaceutical production, accounting for more than half the biopharmaceutical products approved between 2018 and 2022. Using mammalian cells has several drawbacks including the high cost of the cell media, regulatory scrutiny, increased chance of human pathogens and the slow nature of fermenter-based systems for cell cultures.
The use of plants as a source of biopharmaceuticals potentially alleviates many of these issues. Like mammalian cells, plant cells can produce complex PTMs, and many species of plants have long been used in traditional medicine, and many pharmaceutical products are still based on products extracted from plants. These include compounds used in the treatment of Alzheimer’s disease, certain forms of cancer, atrial fibrillation and several other conditions. However, plants can also be used to produce other compounds through genetic modification, including both medical compounds themselves and nanoparticles to deliver drugs and vaccines in the body, though regulation surrounding the growth of GM crops differs substantially based on jurisdiction.
In either case, while plant cell lines can often be used to produce pharmaceutical compounds, this still requires the use of fermenters which means they are not easily scalable. Traditional open-field methods could be used for growing pharmaceutical crops but are subject to biotic and abiotic issues which can cause fluctuations in growth and yield, such as extreme weather events and plant pathogens. Furthermore, some plants used for biopharmaceuticals, such as foxglove, are difficult to grow naturally and suffer from over-harvesting of wild populations. The controlled environment of indoor vertical farming allows for stable growing conditions and thus a more consistent yield of pharmaceutical compounds. Additionally, the stacked growing conditions of vertical farms potentially allows for a larger scale yield per square metre than fermenters and open-field farms.
So far, however, the use of vertical farming for biopharmaceuticals has been limited. It is therefore worth discussing some examples of pharmaceutical plants which could be grown using vertical farming, along with the potential benefits and limitations of using this method for biopharmaceutical production.
Cannabis: Potentially Profitable, Legally Restricted
Of all the plants which have medical utility, cannabis is one of the most widely grown among vertical farms and CEA facilities more generally. The plant was grown by around 9% of vertical farms to the 2019 Controlled Environment Agriculture census, and by 5% of CEA farms according to the 2021 census. Cannabis and compounds derived from the plant are used to alleviate the symptoms of multiple sclerosis and psychological conditions such as PTSD and anxiety, and is also used as a painkiller for those suffering from chronic pain and migraines. It can also be useful as an alternative painkiller for cancer patients who do not respond well to opioids or suffer side-effects from other regular painkillers. There is also some evidence that cannabis can be used to control tremors and alleviate pain in patients with Parkinson’s disease. Which medical conditions cannabis is used to treat can depend largely on the relative content of THC to CBD within the specific strain that is grown.
There is potentially a large profit to be made by growing cannabis. While only 19% of cannabis is grown for medical purposes, the overall size of the cannabis market is very large. The US market for the flowers alone was estimated at 5.1 billion USD in 2017 or 1,500 USD per lbs, over 21,000 times the size per lbs of the US wheat industry. However, the legal status of cannabis makes cultivation for medical purposes difficult to impossible in many jurisdictions. In the UK, licences are only available to grow cannabis with a THC content below 0.2% for use as “industrial hemp”, while otherwise cultivating any part of a cannabis plant is illegal. In the US, cultivation is legal in most states and DC, but both state licences and local permits are needed.
These restrictions exacerbate an issue already present in vertical farming; a lack of standards and best practices established by peer-reviewed studies. Much of the knowledge surrounding cannabis cultivation in indoor environments has been spread by word of mouth, and there is a lack of data determining which techniques provide the best results for yield, how these impact THC and CBD concentrations and how profitable it is to grow cannabis using vertical farms, even where it is legal to do so.
Other Potential Pharmaceutical Plants
While most vertical farms focus on microgreens, salad greens and similar crops, a small proportion also grow ornamental plants. However, many ornamental flowering plants also contain a variety of useful pharmaceutical compounds. One example is the Madagascar periwinkle, Catharanthus roseus, which is well known for its production of alkaloids. Alkaloids are a diverse family of chemical compounds, many of which are used recreationally (such as caffeine and nicotine) or for medical purposes. Over 100 alkaloids are produced by the Madagascar periwinkle, including ajmalicine and serpentine which are produced from the plant’s roots and used to treat circulatory conditions. The plant also produces vincristine and vinblastine, which are derived from the plant’s leaves and used to treat cancers including (but not limited to) acute lymphoblastic leukemia, Hodgkin’s and non-Hodgkin’s lymphomas, Ewing’s sarcoma, and breast cancer.
These anticancer compounds are produced in trace amounts by the plant, and are very expensive (1 million to 3.5 million USD per kilogram as per a 2010 study). The expense of extracting these compounds led to several companies ceasing cultivation of the plant, which in turn resulted in a global shortage of vincristine and vinblastine. While vertical farming cannot directly address the expenses of extracting these chemicals, the controlled indoor environment of vertical farms could allow for experimentation to find conditions to maximise the yield. Indeed, for over a decade various studies have focused on maximising the yield of alkaloids produced by Madagascar periwinkle by cultivating the plant under different light spectra. Recent studies have found that yield can be increased by cultivating the plants under a low intensity monochromatic red light prior to exposure with a UV-A light or exposing the plant to high intensity blue light. Despite the number of papers investigating the impact of light on growth and yield, so far large-scale commercial production of the plant within indoor vertical farms has not been attempted.
Different alkaloids are also produced by other small plants which may be suitable for growth in vertical farms. The lesser periwinkle, vinca minor, is closely related to the Madagascar periwinkle (both are in the family Apocynaceae) and also produces a large number of alkaloids. This includes vincamine, which (along with the semi-synthetic derivative vinpocetine) is used to treat cerebrovascular conditions such as stroke and dementia, and may also have anticancer properties. This flower can be difficult to cultivate due to being sensitive to changes to environmental and nutrient conditions, which could be mitigated by the high level of control provided by vertical farms.
Daffodils, and other plants in the family Amaryllidaceae, also produce an alkaloid called galantamine which is used to mitigate the symptoms of mild to moderate Alzheimer’s disease. This chemical can be produced synthetically, but the process is difficult and expensive, thus extracting the compound from plants can be more cost effective. However, as populations in many parts of the world are becoming older, the demand for drugs to mitigate Alzheimer’s disease is likely to increase and thus there is a need for supplies to increase. As such, vertical farming could allow production to be upscaled in a way that reduces the land area needed.
Alkaloids are not the only family of chemicals with medical purposes produced by ornamental plants. Foxglove species (of the genus Digitalis) produce cardiac glycosides (more specifically the sub-type called cardenolides), with the most widely used being digitoxin and digoxin. These compounds are used to treat various heart conditions by increasing blood pressure while reducing heart rate, and are vital for patients with compromised cardiac function. Furthermore, various compounds extracted from foxglove have been shown to be effective at treating various cancer cell lines. However, due to the utility of foxglove, populations of wildflowers are experiencing over-harvesting. As such, vertical farms could provide a stable, protected population occupying a small land area.
Other plants have more general therapeutic properties. Lavender is widely used for various medicinal purposes and is also commonly added to food for flavour. Probably its most widespread medical use is as an essential oil for aromatherapy to improve sleep, and reduce stress, anxiety, and depression. The effectiveness of these therapies is somewhat disputed, though a 2020 literature review found that lavender is probably useful in aiding mild to moderate depression is fused alongside other treatments. There is also some evidence that lavender essential oil has antimicrobial, antioxidant and anti-inflammatory properties.
Small plants with potential medical properties are not just restricted to flowers, however. Aloe vera is widely cultivated because of the gel contained within the leaves. This gel can be used for a variety of medicinal products, including toothpaste and suntan lotions. However, it is probably best-known as a topical ointment for treating skin conditions, inflammation, wounds, and burns. There is also a large potential market that vertical farms growing aloe vera could exploit. As of 2020, the global market for aloe vera gel was estimated to be 649.41 million USD, with 61% of that being made up by the pharmaceutical industry.
These are just some of the examples of crops with naturally occurring pharmaceutical or medicinal properties with already established industries. Vertical farming may not be appropriate for all of these crops, but they could be a useful source of revenue, especially where growing GM crops is restricted. Small-scale experiments should be conducted prior to production to establish whether doing so is economically feasible (and to establish which growing conditions result in the best yield).
GM Pharmaceutical Crops
The idea of using genetically modified crops for producing pharmaceutical products has been present for several decades. A study published in 1989 demonstrated that human antibodies could be produced by a transgenic tobacco plant, while in 2006 the US Department of Agriculture licenced a poultry vaccine produced by GM tomato plants. The term “pharmaceutical crop” is sometimes used to refer to refer to plants which have been specifically genetically modified to produce pharmaceutical compounds, while biopharming is the practice of using GM crops as bioreactors to produce large molecules for medical purposes. However, these terms can be confusing as “pharmaceutical crops” are also sometimes used to refer to plants which naturally produce small molecules as active pharmaceutical ingredients.
Plants which are genetically modified for the purposes of producing pharmaceuticals largely face similar restrictions as GM crops grown for general consumption. In the UK, transgenic pharmaceutical plants cannot be grown commercially. In 2023, the EU adopted a proposal which allowed some GM plants to be exempted from usual restrictions if they could feasibly be produced naturally or via conventional breeding. However, it seems unlikely that these new rules will impact most GM pharmaceutical crops, as they mostly involve engineering the plants to produce compound which wouldn’t be made naturally by that species. That said, the new legislation is mostly concerned about the use of GM crops for food and animal feed, and indeed EU legislation specifically focused on the use of GM crops for pharmaceutical purposes is difficult to find. Legislation surrounding GM farming in general is far less restrictive in the US, with over 90% of some crops being GM.
Despite this, the US Department of Agriculture considers pharmaceutical crops to have inherent risks that those grown for food do not, and as such they are subject to stricter regulations. The decision to regulate pharmaceutical GM crops more stringently largely came after the biotech company ProdiGene was involved in two contamination incidents in 2002, in which GM pharmaceutical corn was mixed with a soybean harvest. The risk of contamination is one of the main concerns that drives regulation of GM crops in general, however pharmaceutical plants may contain compounds that are harmful to humans or animals (depending on the nature of the crop).
Growing GM crops in contained environments such as indoor vertical farms or greenhouses is likely to decrease the risk of contamination. However, vertical farms also provide the same advantages to GM pharmaceutical crops over greenhouses as to other crops grown for medical purposes. Namely a greater deal of control over the environment which can provide a more consistent yield of pharmaceutical products. However, the most common crops used in GM pharmaceutical farming include tobacco, rice, maize and barley, which are not crops that are typically grown in vertical farming as they are not financially viable. As such, research may be needed to help maximise the yield of these crops, and it remains to be seen if the addition of pharmaceutical compounds will offset the cost of growing these crops. Alternatively, these crops may also be grown using single layer CEA farms that still use hydroponic systems. Furthermore, biopharming has been developed for a range of different crops, including some which are more typically grown in vertical farms such as lettuce. In jurisdictions where commercial biopharming is not currently allowed, the development of indoor vertical farming for these purposes may help sway decision makers to allow the industry to be present in environments with more control and less risk of contamination.
Other Considerations and Milkweed Case Study
Many of the challenges which face vertical farming for food crops will also be present when growing pharmaceutical plants. Specifically, the labour and energy cost of vertical farming can be many times more expensive for vertical farming compared with open field farming, and the initial setup costs can also be much higher than for greenhouses or open field farming. Potentially, these costs could be offset by the high selling price of pharmaceutical compounds, but these compounds also need to be extracted and purified from the plants. For pharmaceutical protein production in GM crops, purification can make up 80% of the cost, and often involves techniques which are specific to each product. For some pharmaceutical products, a potential solution is to develop GM crops containing the desired compound which can be consumed orally. However, this may not be appropriate for all compounds, and as such further analysis of pharma crops in vertical farms is needed to assess their financial viability.
There is currently limited research investigating the economics of growing pharmaceutical crops using vertical farms. However, an experimental study published in 2022 gives an important example of how future research could be conducted. This experiment focused on Euphorbia peplus, also known as milkweed or petty spurge. The sap of this plant contains ingenol mebutate, a compound which was found to be effective at treating actinic keratosis, though the product was withdrawn in 2020 and approval for use in the EU suspended due to an increased risk of skin malignancy. Although this means that growing milkweed for medical purposes is obviously no longer a viable business, the research is still useful as a hypothetical model of a vertical pharmaceutical farm.
The study focused on growing milkweed using a container-model vertical farm using a deep-water irrigation system which was controlled using remote monitoring. The study also measured the impact of different hydroponic substrates (rockwool, coconut fibre and clay beads), light intensities (250 and 500 μmol m−2 s−1) and plant localisation within the rack on growth rate and yield, while three different extraction methods were also developed and total ignenol yield measured. After this, both cultivation and extraction were factored into a budget to analyse economic feasibility by assessing the price of the final product. The results showed that while hydroponic substrate, localisation and light intensity had a significant impact on plant growth yield, the total ingenol content was not significantly different. The study also found that the extraction method with the highest overall cost (Ethyl Acetate at 120 °C) also had the highest yield, and in this case had the cheapest cost per mg of ingenol produced.
The economic analysis showed that the predicted range of income generated by milkweed cultivation varied substantially based on the concentration of the gel produced. The analysis also found that the low biomass and extraction yield of the gel made reaching economic feasibility would be difficult, so experimenting to find which abiotic factors result in the highest yield would be extremely important in determining profitability. It should be noted that this experiment focused on one pharmaceutical product from a single plant using a specific form of vertical farming (container-based). As such, the factors measured here may have different impacts on different plants and on the yield of different compounds. However, it does highlight the importance of modelling and trialling potential pharmaceutical vertical farms for a specific product before investing in larger-scale production.
Another consideration for pharmaceutical crops is minimising the risk of contamination. As discussed above, this is especially important for GM crops, but stopping pests and pathogens from interfering with the production of pharmaceutical compounds is also a more general concern. The controlled environment of vertical farming already reduces this risk compared with open field farms, but increased automation may be desirable because it will reduce the amount of human contact needed for cultivating the plants, and thus the risk of contamination. The increased use of automated systems such as deep-learning, AI and robotics are often discussed in vertical farming, though some of these may not be appropriate for small-scale vertical farms. However, it is currently unknown what scale of vertical farm would be best suited to invest in pharmaceutical plants, regardless of automation. Furthermore, some pharmaceutical plants may be too delicate for some automated systems such as conveyor belts. As such, new or custom systems may have to be designed for these plants, and the effectiveness and cost of automated processes will also likely have to be modelled or tested prior to implementation.
Summary
Currently, the number of crops grown by most vertical farms is limited due to energy, labour and setup costs making the growth of most crops not economically feasible. Even among this small selection of plants, profit margins are often small, and many large-scale farms struggle to reach a suitable return on investment and financial difficulties, including the closure of several high-profile vertical farming businesses over the past decade. Furthermore, vertical farming currently does not receive the same level of financial support as traditional agriculture, which makes expanding into other crops even more difficult.
While this may change as traditional agriculture becomes more challenging due to the impacts of global warming, at present crops grown for pharmaceutical products may provide an additional source of income for vertical farms due to the premium price of these compounds. Additionally, producing pharmaceutical compounds in vertical farms allows for larger-scale production compared with cell cultures while providing more consistent and better protected growing conditions than open field environments.
However, biopharmaceutical crops have their own limitations. Some plants, such as cannabis and GM crops, are either illegal to grow or face heavy restrictions depending on jurisdiction. Meanwhile, many pharmaceutical compounds are only produced in small quantities by the relevant crops, while extraction, purification and dosage in end products can have a large impact on profitability. Inadequate modelling and testing of growth conditions to maximise yield and assess economic viability is a major issue in vertical faming more generally and may be even more important for pharmaceutical crops given these additional complexities.
March 2024