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Molecular Farming – The prospects in developing countries

The article seeks to highlight the immense benefits of molecular farming and the need of commercial scale cultivation, in order to cater to the huge demand of pharmaceutical and agricultural products.

By Prof. P.S. Bisen
January 02, 2010

The requirement for large quantities of economic and safe therapeutic proteins has fueled a growing interest in the production of recombinant proteins in plant bioreactors. The plant systems have been successfully identified as suitable expression systems for the commercial production of human and animal antigenic proteins (Vaccines) for a number of diseases ranging from common cold to AIDS. Such plant-derived vaccines have been found to be safe and effective during extensive clinical trials. Once a widely and commonly grown plant is made transgenic with the antigenic gene, the large-scale cultivation and recovery of the vaccine from transgenic plants would be possible everywhere in the world. The processed vaccines from such sources are devoid of toxic components. Over the last 10 years, several efficient plant-based expression systems have emerged, and more than 100 recombinant proteins and several other edible vaccines have been produced in a range of different plant species. Plants have many advantages over other production systems particularly in terms of practicality, economy and safety.

Molecular farming involves production of pharmaceutically important and commercially valuable biomolecules including proteins in plants. Its purpose is to provide a safe and inexpensive means of mass production of recombinant pharmaceutical items. Complex mammalian proteins can be produced in transformed plants or transformed plant suspension cells. Plants are suitable for the production of pharmaceutical proteins on a field scale because the expressed proteins are functional and almost indistinguishable from their mammalian counterparts. Molecular farming in plants has the potential to provide virtually unlimited quantities of recombinant proteins for use as diagnostic and therapeutic tools in health care and life sciences. Plants produce a large amount of biomass; protein production can be increased using plant suspension cell culture in fermenters, or by the propagation of stably transformed plant lines in the field. Transgenic plants can also produce organs rich in a recombinant protein for its long-term storage. This demonstrates the promise of using transgenic plants as bioreactors for the molecular farming of recombinant therapeutics.

The plants are considered as the most renewable production resources for a variety of proteins, fats, essential amino acids, dyes, drugs, chemicals etc. The advent of various plant biotechnology techniques, such as, modem breeding methods, cell and tissue culture, somaclonal variation, clonal propagation, protoplast culture, somatic hybridization and genetic transformation have played a vital role in establishing plant-based industries for the production of above mentioned value added compounds. Several plant-derived bio­pharmaceutical proteins are ready for commercial production. These products include antibodies, vaccines, human blood products, hormones and growth regulators. Transgenic plants are being raised and cultivated on large scales for manufacturing vaccines against human and pathogenic agents, both viral and bacterial. This approach would prove very beneficial for the developing and the underdeveloped countries.

Plant-derived edible vaccines have an advantage of being used orally. They have been observed to stimulate production of mucosal antibodies more effectively than the injected vaccines. The mucosal immune system is a part of the body's first line of defense against many disease-organisms. A mucosal tissue comprises all lymphoid cells in epithelia and cells lying below the body's mucosal surfaces. The main site of mucosal lymphoid tissues is associated with the bronchial system and gut. To stimulate this system in the gut, an oral vaccine has to be protected from degradation at acidic pH of the intestine (stomach). Stimulation of the mucosal immune system produces secretory antibody i.e. IgA. The secretory antibodies comprise 75% of the total antibody synthesized and secreted in the form of tears, saliva and milk. These properties of the edible vaccine are gifted to by the associated plant tissues, which protect vaccines from degradation in the digestive tract.

In the developing and the underdeveloped countries, the cost of vaccines is a limiting factor. A large majority of people remain unprotected against preventable diseases because they cannot afford. Vaccine production, packaging, delivery, administration by trained people and refrigeration, which are prerequisite for shipment or storage increase its cost very high. Similar economic factors apply also to large-scale vaccination of farm animals.

The modern large-scale vaccines-producing industries use mostly bacteria, yeast, insect and mammalian cells and transgenic animals as production resources. Vaccines expressed in these wild/genetically-engineered systems are essentially processed to remove host proteins, toxins as well as other noxious compounds, which contribute to their high cost. In addition, these production systems are highly prone to contamination by microbes that sometimes evade detection even in the purified vaccines. Hence, these systems can not be considered ideal for the production and delivery of quality and economically viable vaccines. Designing plant-derived vaccines would become an important alternative to meet the increasing market demand of cheaper, safer and quality vaccines. The successful development of vaccines against human animal pathogen (s) depends primarily on establishment of stable transformation procedure for widely and commonly grown crops and ease in scale up of contaminant free production of antigenic proteins.

Production of the vaccines is based on two strategies:

(i) Stable transformation of plant cells with gene(s) encoding antigenic proteins and

(ii) its transient expression.

Transgenic plants, especially of the edible variety, provide an excellent alternative for the production of desirable vaccines. This system also allows easy and economic scale­up of production by cultivating more of these plants in the field. In addition, the continuous refinement of the plant genetic engineering tools and an increasing understanding of plant molecular biology have helped improve the genetic design of plants with greater capacity for production of vaccines, pharmaceuticals and nutraceuticals.

Plant systems used for in vitro expression biomolecules:

Transgenic plants express foreign proteins successfully. Gradually, these plants are replacing the fermentation-based production systems. There are two methods: (i) transient and (ii) stable genome integrated expression of foreign genes i.e. trans genesis of plants.

Targeted expression of molecules: The same plant systems can be used for introducing more than one genes for targeted production of proteins. For example, it is possible to facilitate tissue specific expression of foreign proteins in fruits, leaves, tubers or seeds that we eat in our every day meal. Several stably transformed tobacco plants have been generated for such purposes. Recently, transgenic carrot plant has been generated for production of vaccine against the measles virus, and tobacco plant against cholera. Potato tubers have been transformed with rotavirus that can immunize mice. Cervical cancer is linked to infection with human papillomaviruses (HPV). It is the third most common cancer amongst women worldwide. Efforts are being made to produce transgenic tobacco and potato plants that can raise immunity of women against this cancer which is often caused by human papiloma virus (HPV). A transgenic alfalfa plant has been produced that can save cattle against foot and mouth disease (FMDV).

Hepatitis B is a dangerous virus. Lettuce and lupin plants have been engineered to produce vaccine against this virus. So, if you eat this 'saag' you will be immunized against hepatitis B.

Recombinant human hemoglobin is also in pipeline for large scale production through transgenic plants.

Future prospects

The production of recombinant proteins in plant systems has great potential as effective tools for plant research and commercial biotechnology. During the last few years, there has been an increasing interest in the field of gene regulation and protein synthesis in different plant systems that may be used as a novel approach for production of some important therapeutic drugs or proteins.

Recent improvements/developments in this area have significantly increased its utility and enabled various groups to explore the possibilities of production of recombinant proteins from a variety of different plants, which can be directly or indirectly used for various pharmaceuticals, nutraceutical and therapeutic purposes.

Much effort is now being devoted to the commercialization of this technique particularly by adapting the strategies to increase yield and quality of the desired proteins. There are some hurdles related to the biosafety concerns and environmental impact which directly/indirectly affect popularization of mass cultivation of genetically modified crops. Production of some of the important therapeutic proteins in a suitable plant system with better yields significantly reflects the success in the technological achievements in this area but still some of the hurdles related to its commercial scale cultivation are yet to be overcome.

The author is a former member of the University Grants Commission, New Delhi and former Vice-Chancellor of Jiwaji University, Gwalior. At present, he is Chairman of the Vikrant Group of Institutions.


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