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16-31 August 2006  
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Home - Research - Article

Medicine Trees

With more than 300 plant-made pharmaceuticals (PMPs) under various stages of discovery, plants are now gaining widespread acceptance as a platform for protein production. There is no doubt that PMPs are soon going to be the new buzzword in the biotech industry, Sushmi Dey discovers

Advances in biotechnology aided in the production of therapeutic proteins essential in a wide range of pharmaeuticals like monoclonal antibodies, enzymes and blood proteins. Since the demand for these biopharmaceuticals is expected to increase, researchers all over the world are looking at ways to ensure that they will be available at significantly larger amounts and on a cost-effective basis. One such solution comes in the form of plant-made pharmaceuticals (PMPs), which are cheap to produce and store, easy to scale up for mass production and safer than those derived from animals.

The plus factor

The use of plants for medicinal purpose dates back to thousands of years, but genetic engineering of plants to produce desired biopharmaceuticals is a much more recent phenomenon. In normal circumstances, drugs are synthesised through strong chemical reactions or taken from natural sources such as texol or curcumin. The conventional system in place for the production of commercial protein has relied on microbial fermentation and mammalian cell lines. But according to studies, these systems have disadvantages in terms of cost, scalability, and safety that have promoted research into alternatives.

PMPs are a category of pharmaceutical proteins that are produced in 'live plants'. These live plants are genetically modified to produce drugs. "Plants can produce large amount of proteins in them," says Dr V Siva Reddy, Group Leader, Plant Transformation Group, ICGEB. Plants can express a protein in a very profitable manner by manipulation of genes or by the introduction of genes required to express a particular protein. Hence, pharmaceuticals can be produced in large quantity, and purity can be expressed in high levels.

Plants have emerged as one of the most promising general production platform for biologics. Plants allow cost-effective production of recombinant proteins on an agricultural scale, while eliminating risks of product contamination with endotoxins or human pathogens. In addition, with the use of plants in the production of recombinant protein, vaccine candidates can be expressed in edible plant organs, allowing them to be administered as unprocessed or partially processed material. However, in matters of efficacy, they are equivalent to the conventional drugs, informs Reddy.

Some plants used for PMP
Model plants Arabidopsis thaliana Range of variable mutants, accessible genetics, ease of transformation Not useful for commercial production (low biomass)
Simple Plants
Physcomitrella patens, Chlamydomonas reinhardtii, Lemna
Containment, clonal propagation, secretion into medium, regulatory compliance, homologous recombination in Physcomitrella Scalability
Leafy crops
High yield, established transformation and expression technology, rapid scale-up, non-food/feed Low protein stability in harvested material, presence of alkaloids
Alfalfa, clover High yield, useful for animal vaccines, clonal propagation, homogeneous N-glycans (alfalfa) Low protein stability in harvested material, presence of oxalic acid
Lettuce Edible, useful for human vaccines Low protein stability in harvested material
Maize, rice
Protein stability during storage, high yield, easy to transform and manipulate  
Wheat, Barley Protein stability during storage Low yields, difficult to transform and manipulate
Economical, high biomass, expression in seed coat Low expression levels, difficult to transform and manipulate
Pea, Pigeon Pea High protein content Low expression levels
Fruits and Vegetables
Potato, Carrot
Edible, proteins stable in storage tissues Potato needs to be cooked
Tomato Edible, containment in greenhouses More expensive to grow, must be chilled after harvest
Oilseed rape, Camelina sativa
Oleosin-fusion platform, sprouting system Lower yields

According to studies published in 2004

Technology behind PMPs

In the process of producing PMPs, plants themselves act as factories to manufacture therapeutic proteins. Special proteins or compounds are expressed in different parts of plants, some specific tissues, such as whole leaves, whole seeds, or even specific regions of seeds or leaves. The whole process is meant to incorporate the desired foreign gene into the genome of the plant to create a transgenic plant. "It is preferred to produce those pharmaceuticals, which are protein, carbohydrate or lipid based, specifically those which can be expressed and stored in roots, seeds or small inclusion bodies in the cell," explains the Director of Department of Biotechnology (DBT). After the plants are harvested, they go through a series of processing steps that extract, separate, purify and package the therapeutic proteins.

The production of the desired protein in a plant requires a number of complicated molecular biology techniques, where the propriety promoter is fused to the gene of the target protein, forming an expression cassette. With these transgenic techniques, the proprietary expression cassette is introduced into plant cells. The transformed cells are then cultured as suspension cells or regenerated as transgenic plants. High protein expressers are selected and used for protein production. The refined therapeutic proteins are ultimately used as active pharmaceutical ingredients (APIs) in many life-saving medicines and are regulated by the FDA.

In PMPs, plants are the factory or storehouse, where proteins, that will be used in subsequent manufacture of medicines, as the API in a pharmaceutical product, are produced. The normal techniques of extraction, purification and formulation, which are used in normal pharmaceutical companies, are all followed even in the case of PMPs. Though therapeutic proteins produced in PMP field trials are usually not intended to be administered via food, some of the PMPs can be taken orally, while some have to be injected.

Production platforms

There are several plant-based protein production platforms that rely on protein expression from nuclear genes and viral vectors in leaf, seed, tuber and tissue culture cells. However, each of the platforms has its own strengths and weaknesses. Crops such as corn, tobacco, rice, soy, wheat, barley and maize are genetically altered to yield proteins in different parts of the plant. Scientists prefer to opt for genetically modified food crops because of the good understanding of genetics, agronomics and environmental impact of the crops.

Leafy crops are advantageous in terms of biomass yield, but since proteins expressed in such leaves tends to be unstable, the harvested material has a limited shelf life and therefore, must be processed immediately after harvest. However, proteins that are expressed in cereal seeds are protected from proteolytic degradation. Hence, such proteins can be preserved for three years at room temperature and for at least three years at refrigerator temperature without much loss of activity. Prodigene, an industry leader in cereal based protein production has chosen Maize because of its high biomass yield.

Yet another plant group which is considered as good hosts for protein production are oil crops, as oil bodies can be exploited to simplify protein isolation. As per published records, SemBioSys Genetics has developed oleosin-fusion platform, in which the target recombinant protein is produced in oilseed rape as a fusion with oleosin. The Finnish biotech company, Unicrop is also developing an oil seed platform. However, they are attempting to isolate recombinant proteins from rapidly developing sprouts cultivated in bioreactors.

Tobacco helps

Surprisingly, tobacco forms a well-established expression host for which robust transformation procedures are available. Tobacco has a high biomass yield and rapid scalability which makes it a popular choice for commercial molecular farming. "Tobacco is also preferred since it is not a food or feed crop and hence carries reduced fear for transgenic material or recombinant proteins contaminating feed and human food chain," explains Reddy. However, the high content of nicotine and other toxic alkaloids, which are harmful, need to be completely removed during downstream processing steps. Tobacco, as a platform, has also been adopted by several biotech companies, across the world. According to the latest published records, Planet Bio-technology and Meristem Therapeutics are companies who have PMPs with tobacco as a platform with products in Phase II clinical trials.

Fiddling with nature has its own limitations and hence, risks. With new technology, newer regulations to save the biosphere and environment are a must. While a number of Indian pharmaceutical companies are willing to take initiatives on PMPs, they could not pursue it due to the lack of clarity on bio-safety. The procedure involved in PMPs technology needs more stringent regulatory mechanism than the normal transgenic plants. The regulations for PMPs include issuing of the permit by the federal government after R&D and limited confined trials, regulations on the confinement measures, training for growers and penalty clause. Regulatory oversight, coupled with individual companies' stewardship procedures, are also designed to keep PMPs separate from the food chain so that these proteins are not mixed with or consumed as food. The plants are grown under highly regulated conditions in confined growing environments to avoid any biohazards. However, PMPs are otherwise safe, if all standard purity protocols are followed and the protein matches with the gold standard drugs. Though several challenges remain to be met to bring PMPs to market, researchers believe that those plants with their safety benefits and economical factors will soon surpass traditional production systems for pharmaceutical proteins. "Future of PMP is bright but we must lay down bio-safety guidelines," asserts Director, DBT.

In the future

Stunning advances in areas of immunology, genomics and molecular screening have dramatically increased the hope for PMPs in the pipeline. But the truth is that the pipeline is not flowing as smoothly as it should because of the daunting costs of building adequate production facilities. "Any new technology is expensive in the beginning but with increase in volumes, competition and time, the price will come down," opines Reddy. Agrees the Director from DBT, "Once the procedures are standardised and streamlined, PMPs can be very cost-effective," she says. She also feels that there is a good potential in the technology but in India, it is not being taken up in an aggressive manner as it has been done in US and France. However, the industry is still optimistic about it.

Researchers believe that one of the keys to success will be the level of expression of the recombinant protein in plants. The expression level will affect the cost of growing, processing, extraction, purification and waste disposal.



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