Publication date: May 18, 2023

Molecular farming is a field of biotechnology that promotes the use of plant crops as biofactories for the production of high-value bioproducts using biotechnology. The term also includes the genetic modification of agricultural products for the production of proteins for commercial and pharmaceutical purposes. The transformation of non-viable crops into efficient biofactories is aimed at an effective solution in the context of a modern bioeconomy and at the same time supporting a sustainable rural development strategy through, among others, the best possible synthesis of plants with drugs.

The term “molecular farming” was coined in 1986, but it took three decades for the FDA (Food and Drug Administration) to approve the first plant-derived therapeutic protein. Carrot cell protein turned out to be a valuable tool in the treatment of a rare genetic disorder, which is Gaucher disease, which causes abnormal breakdown of fats in the human body, and therapeutic protein of plant origin helps restore proper metabolic function (research by the Israeli pharmaceutical company Protalix BioTherapeutics has shown this fact). Plant-derived pharmaceutical products have received a lot of attention in recent years due to the increasing demand for clinical applications in recent years.

This groundbreaking FDA approval paved the way for further research and applications of molecular farming in the field of therapeutic protein production. The development of molecular farming technology also opens up the possibility of producing other valuable therapeutic proteins that can be used in the treatment of various diseases, including cancer, immune system and metabolic diseases. The use of plants as protein factories can contribute to greater availability and safety of drugs, especially in countries with poor production infrastructures. It is worth noting that the monoclonal antibodies produced by plants against HIV and Ebola have shown very few side effects, the most common being mild fever. However, in the early years of the study, it turned out that the percentage of vaccinated people who developed an immune response was much lower compared to clinical trials using standard vaccines.

Molecular farming is the next step in the field of Alt Protein. The Alt Protein Project is a global student movement, created by the Good Food Institute, aimed at university education, research and innovation in the field of proteins. Students mainly conduct scientific research that improves the sensory and functional properties of new protein products or create educational programs. At the core of the project there is the idea that students can make a real difference to their universities and the way they produce food – creating a system that is sustainable, safe and fair. In addition, the aim of the project is to develop an alternative protein, i.e. meat, eggs or dairy products that are of plant origin, cultivated or derived from fermentation.

Physiological properties of plants, such as high production efficiency or the absence of accidental infectious agents affecting mammals, are important factors that enable plants to act as biofactories in biomolecular production systems in the bioeconomy. The ability to produce recombinant proteins or small metabolites is one of the main bioproduction applications of plants. Recombinant proteins are proteins obtained from recombinant genes that are assembled from different fragments of nucleic acids. The use of these proteins enables the effective production of peptides that occur in limited amounts in natural conditions. Examples of such proteins are insulin used in the pharmaceutical treatment of diabetes and rennet, which is essential for the production of cheese. In the case of metabolites, metabolic engineering of plants allows for the redirection of metabolism, i.e. metabolism in the body, to produce various small molecules, such as drugs, additives or antioxidants. This approach is also known as plant metabolic engineering.

The use of genetic recombination technology allows the introduction of genes encoding desired proteins into organisms, such as bacteria or cultured cells. These organisms become factories that efficiently produce recombinant proteins on a large scale. This method of recombinant protein production greatly increases the availability and yield of these peptides, which is crucial for pharmaceutical and industrial use.

By using recombinant genes, insulin and rennet production can be scaled up to meet the demand for these substances. Insulin is essential for people with diabetes, and rennet is a key ingredient in the cheese making process. Thanks to recombinant proteins, it is possible to provide these substances in larger quantities, which contributes to ensuring their wide availability and stable production.

Plant biofactories are playing an increasingly important role in the recombinant protein industry. Back in 1997, ProdiGene commercialized the first plant-derived protein, chicken avidin, made from corn. In the same year, Chong and colleagues produced recombinant human milk casein in potato plants. Other types of proteins, such as amylases, phytases and hydrolases, are also produced in transgenic plants and have applications in various industries.

However, until now, biotechnological production, with few exceptions, has been dominated by microbial and mammalian cell culture systems. There are two interrelated reasons for this phenomenon. The first is the technical difficulties associated with the introduction of precise genetic modifications in plants compared to microorganisms and cell cultures, and in Europe this is additionally affected by the strict regulation of genetically modified organisms. The second factor, which also affects the first, is the lack of specialized plant biofactory platforms.

In the past, the concentration of biotechnology activities on a few specialized organisms has played a key role in the successful development of microbial and mammalian-based biofactories. The clearest example of this approach is the Escherichia coli bacteria, which is the focus of more than 40 years of industrial and academic research. As a result of this research, adaptations and improvements of E. coli (e.g. reduced recombination, susceptibility to viral infections) were made, which made these bacteria preferred for biological production. Similarly, the optimization of standard platforms for different organisms, such as yeast or the Chinese hamster ovary (mammalian cell) cell line, enabled the identification of functional indicators to improve the quality and yield of bio-based products. Once identified, these indicators can easily be transferred to more specialized organisms, however, this requires a prior focus on the appropriate platforms.

In a recent study by a team at Stanford University, 34 yeast DNA modifications were made to synthesize a molecule that has the ability to affect human muscles, glands and tissues. This innovative technique allows the use of yeast as bioreactors for the production of drugs, antibodies and vaccines. However, yeasts are not the only organisms used for this purpose. Other bioreactors used for the synthesis of drugs, antibodies and vaccines are, for example, insect cells and eggs. Chicken eggs are commonly used to grow flu vaccines. This process involves the propagation of a weakened version of the flu virus in chicken eggs, which promotes its growth and the production of vaccines.

Until recently, no model plant species has been selected to optimize plant bioproduction. For about 20 years, the history of molecular farming has been characterized by a dispersed selection of many different plant species as platforms, from edible plants to industrial and less common crops. However, plant species belonging to the genus Nicotiana, and in particular cultivated tobacco and Australian dwarf tobacco, are currently considered the most suitable for widespread use in molecular agriculture.

Optimizing these plants as biofactories opens up new possibilities for the production of alternative proteins, drugs, vaccines and other biotech products. Work on molecular farming, focusing on the development of plant biofactories based on selected species, is now an area of intense research and innovation aimed at accelerating progress in the field of bioproduction and contributing to sustainable development and accessibility of innovative products to society. They open the door to a wide range of applications in medicine, agriculture, industry and the environment. Biofactory plants can also be used to produce enzymes, biopolymers, biofuels and other sustainable chemicals that can replace traditional petroleum-derived feedstocks.

Over the past few years, the Good Food Institute has produced dedicated reports for different categories of alternative proteins on the market, such as plant-based, precision-fermented, and cell-cultured meats and other products. In April 2023, GFI announced the introduction of molecular farming as a potential fourth pillar in the market. This method involves the production of animal protein using seed crops. Geneticists inject animal DNA directly into seeds, turning crops into protein factories. Growing wholesome proteins from the soil is the most efficient way to produce them for human consumption.

Adding a fourth pillar to the alternative protein market is a response to the growing interest in molecular farming. In early April 2023, Moolec announced that their genetically modified safflower plants have been approved by the Animal and Plant Health Inspection Service as not threatening larger pests than non-genetically modified safflower plants.

Motif Foodworks, a specialist in bioengineered ingredients, announced earlier this year that it would partner with IngredientWerks to support the production of their patented ingredient HEMAMI™ (the equivalent of myoglobin in beef), which is grown in corn. According to GFI, there are currently 12 companies worldwide using this technology to produce a variety of products, such as casein and lactoferrin, animal-free dairy proteins for cheese, ice cream and yogurt, and growth factors for cell-grown meat.

Moolec is one of the leading entrepreneurs in the field of molecular farming, and their successes, such as the approval of genetically modified plants, bring advances in the availability of animal-derived proteins. The IPO by Moolec, as the first company operating in this area, indicates the growing interest and confidence of investors in molecular agriculture.

With a growing number of companies using molecular farming technology to produce a variety of products such as dairy proteins, growth factors and more, the alternative protein sector is evolving rapidly. Thanks to such innovations, new opportunities for highly nutritious foods are being developed that are more sustainable and greener.

To sum up, molecular farming as the fourth pillar on the market of alternative proteins brings innovative solutions in the production of proteins of animal origin. Companies such as Moolec and Motif Foodworks are pioneering this technology, expanding the range of protein alternatives available. This makes the alternative protein sector more diverse and promising, contributing to the development of sustainable and organic food options.

While molecular farming has great potential, there are still technical and regulatory challenges to overcome. Further research and development of this technology is needed to ensure the quality, efficacy and safety of plant-derived therapeutic proteins. However, there are already promising prospects for this approach, which could contribute to a revolution in drug production and improved healthcare around the world.

The work on molecular farming and plant biofactories is still being developed and requires further research, investment and collaboration between the scientific, industrial and government sectors. However, the prospects are promising, and advances in plant biotechnology can contribute to solving many of today’s challenges related to food production, health and sustainability.

Molecular farming offers a promising alternative to traditional drug and vaccine production methods while minimizing environmental and climate impacts. The use of plants as replacement biofactories is based on a simple premise: they are cheap and easy to grow. Plants only need three basic elements: light, water and soil. Certainly in the future it will be necessary to develop new procedures and principles of sustainable molecular agriculture. However, current analyzes and tests show very promising results.

Legal aspects of biotechnology

The introduction and implementation of legal regulations regarding biotechnology is necessary for the safety of the biological environment and the people living in it. Matters related to molecular plantations are also regulated by law to ensure the safe and responsible development of this technology and to protect social and economic interests. Molecular plantation laws may include:

•          Safety and risk assessment: Regulations defining risk assessment procedures and standards related to the cultivation and marketing of genetically modified organisms (GMOs). The aim is to minimize potential threats to human health, the environment and biodiversity.

•          Ethical and social issues: Laws may include principles for the ethical and responsible use of molecular technologies, such as the protection of animal rights, the dignity and integrity of organisms, principles of social justice, and public participation in decision-making.

•          Labeling and Tracing: Some jurisdictions require GMO products to be labeled to allow consumers to make informed choices. In addition, regulations may impose requirements for the traceability and identification of GMOs at the stage of production, processing and distribution.

•          Intellectual property: Molecular plantation regulations may include aspects related to patents, copyrights and other forms of intellectual property to protect innovation and encourage research and development in the field.

•          International Trade: Many countries regulate the import and export of GMOs under international trade agreements and regulations, such as the Cartagena Biosafety Protocol.

Legal regulations in the field of molecular plantations therefore serve to secure the interests of various parties, ensure safety and responsibility, and promote the sustainable development of technology. The established existing organizations and institutions have introduced international standards of conduct in the field of biotechnology, the most important of which are:

– defining the conditions for the contained (laboratory) use of genetically modified organisms,

– the deliberate introduction of genetically modified organisms into the environment for experimental and commercial purposes,

– placing on the market products containing genetically modified organisms,

– the health and safety conditions of persons directly involved in these activities, as well as bystanders.

The Polish legal act regulating the above-mentioned issues is the Act of 22 June 2001 on microorganisms and genetically modified organisms.

From the Act we learn, among other things, on techniques leading to genetic modification, risk assessment for human health and the environment – which implies the obligation to determine the harmful effects that may occur, the likelihood of their occurrence and their severity, description of the activity performed during the contained use of GMMs or the contained use of GMOs, including the determination of their scale; determination of the method of handling waste and sewage generated during the contained use of GMMs or contained use of GMOs, or determination of ways to counteract threats and their potential effects.

The provision that regulates the issue of unlawful GMO cultivation is, in turn, Art. 59a, according to which:

“1. Who, contrary to the obligation set out in Art. 49e sec. 1, cultivates GMOs without an entry in the Register of GMO Crops or cultivates GMOs contrary to the conditions and manner specified in the entry in the Register of GMO Crops, shall be subject to a fine and imprisonment for up to 3 years.”

European Union regulations in respect of the issue of genetically modified organisms

Genetically modified feed or genetically modified feed ingredients must be authorized to be placed on the market or cultivated in the EU in accordance with Regulation (EC) No 1829/2003 on genetically modified food and animal feed.

Legal aspects regarding genetically modified organisms are also regulated by, among others:

•          Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC,

•          Convention on Biological Diversity,

•          Regulation (EC) No 1830/2003 of the European Parliament and of the Council of 22 September 2003 concerning the traceability and labeling of genetically modified organisms and the traceability of food and feed products produced from genetically modified organisms and amending Directive 2001/18/EC.

Convention on Biological Diversity

The provisions of the Convention require the protection of the entire diversity of breeds and species of domesticated plants and animals as particularly valuable for the future of agriculture and breeding. In addition, the Convention defines the meaning of certain terms that are binding for signatory states, such as:

• biotechnology – any technological solution that uses biological systems, living organisms or their derivatives, manufactures or modifies specific products or processes or provides goods and services,

• genetic material – any plant, animal or microbiological material or of other origin, containing functional units of heredity,

• biological resources – genetic resources, organisms and their parts, populations and any other living elements of the ecosystem that may be used or of value to humanity now or in the future,

• genetic resources – genetic material of actual or potential origin values.

Article 1 of the Convention states that:

“The objectives of this Convention, in accordance with its relevant provisions, are the conservation of biological diversity, the sustainable use of its components and the fair and equitable sharing of benefits arising from the exploitation of genetic resources, including through appropriate access to genetic resources and appropriate transfer of relevant technologies, taking into account all rights to these resources and technologies, as well as adequate funding”.

Regulation (EC) No 1829/2003 of the European Parliament and of the Council of 22 September 2003 on genetically modified food and feed.

This Regulation is aimed at ensuring a high level of protection of human health and the environment, as well as providing consumers with correct information on the presence of genetically modified organisms (GMOs) in food and feed. The provisions of the Regulation regulate issues such as; safety assessment – because the Regulation introduces risk assessment procedures for GMO products before they are placed on the EU market. Comprehensive scientific studies are also carried out to assess the safety of GMOs for human health, animals and the environment.

In addition, prior to placing GMO products on the EU market, it is necessary to obtain a marketing consent. GMO owners must apply and provide the necessary data to carry out a risk assessment. The Regulation also requires the labeling of food and feed containing or consisting of GMOs above a certain threshold (0.9% for most ingredients). Labeling is intended to enable consumers to make informed choices.

The legislation also regulates the systems for tracking and identifying GMOs in the supply chain to ensure they are traceable.

In terms of consumer information, the Regulation requires that information on the presence of GMOs in food and feed be made available to consumers, both through labels and other forms of communication. EU Member States are responsible for monitoring and controlling the placing on the market of GMOs and GMO products on their territory.

In conclusion, Regulation (EC) No 1829/2003 aims to ensure consistent standards and regulations on GMOs in the EU to protect consumer health and rights and ensure transparency and accountability in the use of biotechnology in food and feed.

Molecular plantations and patent law

Molecular plantations and patent rights are closely related as molecular technologies often lead to patentable inventions and innovations. Patent law allows individuals and companies to obtain a monopoly on the use and exploitation of their inventions for a limited period of time.

In the case of molecular plantations, inventions may include things like: new methods of genetic engineering, genetic sequences, genes, genetic constructs, new varieties of plants or animals, as well as other innovative technologies related to biotechnology. In order to obtain a patent for an invention related to molecular plantations, the inventor must meet patent criteria such as novelty, inventiveness and industrial applicability. In addition, some jurisdictions have specific requirements for biotechnology patents that may include ethical aspects, such as restrictions on the patenting of living organisms or the use of biological materials derived from them.

Patents for molecular technologies in agriculture and horticulture are important to encourage research, development and investment in innovative solutions. They protect the interests of inventors and allow them to use their inventions commercially for a limited period of time. At the same time, patent laws must strike a balance between protecting inventors and access to technology, sustainability, environmental protection and public health.