Molecular Farming – How Plants Produce the Vaccines of Tomorrow

Cornelia Eisenach tells us about molecular farming

Molecular farming is a new technology that uses plants to produce large quantities of pharmaceutical substances such as vaccines and antibodies. It relies on the same method used to produce genetically modified (GM) crops – the artificial introduction of genes into plants. A number of vaccines, antibodies and other therapeutic substances made in plants such as tobacco, maize, potato and carrot are already commercially available or in advanced clinical trials[1]. Producing pharmaceuticals in plants is easy and efficient compared to conventional production methods. Typically, animal or microbial cell cultures are used to produce vaccines but costs associated with maintenance, safety, storage and transport are 80% higher compared to plant-derived vaccines[2].

The technology used to manufacture plant-made pharmaceuticals is similar to that used in GM crop production. The genetic information necessary to make the therapeutic substance is carried on a DNA molecule. During a process called transformation (Figure 1, step 1), this DNA molecule is introduced into the plant where it becomes part of the plant genome. The genetic information carried on the incorporated DNA molecule is read by the plant protein-making machinery (step 2 in picture below) and used to produce the pharmaceutical along with other plant proteins. In this way the plant acts somewhat as a bioreactor, producing large quantities of pharmaceutically active substances.

The latest landmark in the development of pharmaceutical-producing plants sees a tomato-derived vaccine against cholera and hepatitis C[3]. Researchers from the Universidad Catόlica in Santiago, Chile, have combined genetic sequences of these two pathogens and introduced them into plants. The tomato plants then produce key proteins of both pathogens. These are the same key proteins found in conventionally created vaccines using cell cultures from animals or microbes. One of the advantages of the tomato-derived vaccine is that it is easily stored in the seed of the tomatoes themselves, according to lead researcher Patricio Arce[4].

So does this mean that in the future we can eat our vaccines with our greens? This was the way molecular farming, or ‘pharming’ as it is sometimes referred to, was envisaged when the first studies were published nearly two decades ago. However, in a review article[5], Edward Rybicki, a microbiologist from the University of Cape Town, states, ‘…even though oral dosing is still a desirable feature, the product itself will have to be processed to some extent, [that is] formulated in a reproducible way.’ In this case the pharmaceutical substances are extracted from the plant (step 3 in picture above), further processed (step 4 in picture above) and then conventionally administered, for example through a pill, thus ensuring equal dose and reproducible results.

Producing vaccines in plants however, has a drawback because of the associated contamination risk for food crop production. “For instance, if a vaccine were consumed inadvertently, it could lead to desensitisation so that vaccinations would eventually cease to work. There is also the risk that the pharma plants could be eaten by animals, or that the active substances could enter the groundwater and lead to harmful effects.” says Margret Engelhard from The Europäische Akademie in an interview with a European GMO (Genetically Modified Organism) safety website[6]. The first public incident highlighting the bio safety issues that surround molecular farming happened in 2002 in the USA. A soya field was found to be contaminated with transgenic maize producing the pharmaceutically-active substance trypsin causing the complete harvest of 13,500 tons of soya beans to be destroyed. Hence, research is moving towards non-foods such as tobacco.

Tobacco was used for the development of an HIV-neutralising antibody to prevent virus transmission during intercourse[7]. The plant-derived antibody, made into a gel, can be applied to the vagina to prevent HIV transmission whilst not affecting fertility and was targeted for phase I clinical trials in 2009. This treatment is an outcome of an EU-funded project called PharmaPlant involving more than 40 research groups across European countries. One of the project’s main objectives was to address health inequality in developing countries. In an interview during the project’s 2004 launch Julian K-C Ma of St. George’s, University of London said, “The major burden of disease is in developing nations where access to many vaccines is very poor.” It is envisaged that pharmaceutical-producing plants will be grown and processed where they are needed and thereby aid access to otherwise unaffordable treatments in developing nations.

However, establishing molecular farming to make vaccines cheap and easy to access where it is most needed has proved difficult. This is not only because of the generally low public acceptance of GM plants, but also because of the small scale of industrial investment. “It would be a push to make pharmaceutical companies switch their production methods, because they’ve invested so much in existing systems”, Ma explains[8]. Nevertheless, the industry is growing, especially in the USA, and is expected to be worth $80 billion globally by 2025[9].

Apart from low-maintenance and cost-efficiency, another advantage of GM-plant made therapeutics lies in the flexibility to respond to fluctuations in demand. Researchers from the vaccine company Medicago Inc., Canada, have worked to establish a tobacco-based platform which can be used to quickly respond to increased demands in case of influenza (flu) pandemics such as the swine flu outbreak in 2009. In an article for the Plant Biotechnology Journal[10] the researchers state that the current, commercially manufactured flu vaccine ‘relies on the culture of live viruses in embryonated hens eggs…and the full process from the identification of new [virus] strains up to the filing and release of the vaccine product is completed within 4-6 months.’ However, a short response time and a big production capacity are vital in case of a flu pandemic. Therefore the researchers developed a platform in which so called ‘virus-like particles’ are produced in large quantities in tobacco plants. Virus-like particles look like normal particles from the outside but lack the genetic material inside (pictured), thereby, they lose their pathogenicity but are still useful for vaccine production. The virus-like particles accumulate at high levels in tobacco plants and when extracted can be purified to yield large quantities of high quality vaccine. In this way the researchers managed to produce a vaccine against the virus strain responsible for the 2009 A/H1N1 flu pandemic, only three weeks after its genetic sequence became available.

As with any new technique, molecular farming had and still has its teething problems. The risks of cross-pollination and food crop contamination have to be addressed, for example by using non-food plants or indeed, moss and plant cell cultures that can be grown safely in a contained environment. Cost-effectiveness is an important consideration for molecular farming; however this new way of producing pharmaceuticals may also improve the world’s response to pandemics of ever-mutating viruses. Furthermore, it has the potential to contribute to improving global health equality.

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