Recombinant Pharmaceutical Manufacturing From Plants Biology Essay

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On October 15th 2010 the meeting "Recombinant Pharmaceutical Manufacturing from Plants - The Future of Molecular Farming" hosted by EuroScicon was held at BioPark Hertfordshire, Welwyn Garden city, UK. The scientific program of this very eventful meeting was wide ranging and hence covered diverse aspects of Biopharming. The following highlights thereof have been presented: Safety issues in Biopharming, co-expression of multiple proteins, steps towards vaccine generation, engineering of secondary metabolites and medicinal plants. This report summarizes the stimulating scientific presentations and fruitful panel discussions which subsequently arose during and after this event.

Keywords: Biopharming, Pharmaceuticals, Recombinant proteins, Plant vaccines, Bio containment

In his opening remarks the Chair, Ian Graham, CNAP Director & Weston Chair of Biochemical Genetics, University of York, UK, started with an overview of Recombinant Pharmaceuticals. He emphasized Biopharming as a vast area with countless possibilities waiting for scientific exploration, specifically areas like antibodies, recombinant proteins, metabolites, development of platform technologies and the public opinion towards Biopharming.

Co-expression of multiple proteins

The opening lecture on "Development of a virus-derived system for the co-expression of multiple proteins at defined levels in plant cells" was given by George Lomonossoff from the John Innes Centre, UK. He addressed a major challenge in the development of plants as bioareactors: The design of a system that can direct the synthesis of multiple proteins within the same cell at defined and differing levels. Major challenges for stable expression systems consist in time consumption, variable levels of expression and difficulties using various screening methods. Transient expression systems offer several advantages, particularly transgene expression in only a few days using mature plants with demonstrated success for single peptides. George Lomonossoff presented a transient expression system based on a deleted version of Cowpea mosaic virus (CPMV) RNA-2, CPMV-HT, which permitted an extremely high-level and rapid production of proteins without viral replication [1]. The system involved insertion of the gene to be expressed between a modified 5′ untranslated region (UTR) and the 3′ UTR from CPMV RNA-2. Alteration of AUG codon was found to significantly enhance the translation level of the inserted transgene. Retaining the recombinant proteins within the endoplasmic reticulum also helped to increase expression levels. Co-expression of 4 structural proteins from bluetongue virus (BTV) to produce virus-like-particles (BTV-VLPs) for immunological analysis was part of the discussion.

Chloroplast-expressed antigen-vaccines

Andreas Lössl from the University of Natural Resources and Applied Life Sciences, Vienna, AT, gave a talk on plastid-derived vaccine antigens. Chloroplast transformation can address the risk of transgenic pollen flow, as pollen does rarely contain plastids. Furthermore the plastid genome allows to express complete operons (e.g. phbA,B,C), and by this it makes possible to produce multiple antigens by one successful step of transformation. An additional advantage of this organelle transformation technique is the extremely precise insertion of transgenes and absence of silencing effects. Additionally, an inducible expression system is available, to regulate plastid-derived protein production by ethanol induction. This novel approach allows for a controlled expression of transgenes with pharmaceutical impact, and thus plastid-based systems can pave the way towards affordable pharmaceuticals for developing countries.

A recent development is the expression of human papillomavirus (HPV) L1 capsomeres in tobacco chloroplasts. Various types of HPV are causatively associated with cervical carcinoma which is the second most common cancer in women worldwide, particularly in developing countries. Capsomeres have recently been demonstrated to be highly immunogenic structures. Compared to VLP-based HPV vaccines they offer a number of advantages as a potential cost-effective alternative. A modified HPV-16 L1 gene was expressed as a protein which retained the ability to assemble to capsomeres in tobacco chloroplasts [2]. Assembly of capsomeres was examined and verified by cesium chloride density gradient centrifugation and sucrose sedimentation analysis. An antigen capture enzyme-linked immunosorbent assay confirmed the formation of capsomeres by using a conformation specific monoclonal antibody which recognized the properly assembled L1 proteins. These results present the possible production of a low-cost second-generation vaccine from plastids, against cervical cancer.

Genetic engineering of secondary metabolites

The health benefits conferred by numerous secondary metabolites have led to several approaches to elevate their levels in foodstuffs. Two talks focused on health promoting polyphenols and carotenoids, as follows:

Cathie Martin from the Norwich Research Park, UK, reported the potential of plant science to improve preventative medicine to combat chronic diseases. Epidemiological studies have demonstrated the efficacy of diets enriched with fruits and vegetables to reduce the incidences of chronic disease due to their contribution of important phytonutrients which serve to promote antioxidant defense mechanisms. Polyphenols are one of the examples, which have been shown to decrease the risk of cardiovascular disease and cancer. Such foods could benefit consumers in both developing and developed countries. Flavonoids are a large group of polyphenolic compounds. Based on their core structure they can be grouped into different classes: chalcones, flavonols, and anthocyanins. In nature more than 6,000 different flavonoids have been identified, which are effective hydrophilic antioxidants. The health protective properties of anthocyanins contained in many commonly consumed fruits and vegetables could be increased in order to yield better health benefits. Cathie Martin and colleagues succeeded to produce tomato fruits that accumulated anthocyanins at levels considerably higher than attained in earlier studies. Another effect in genetically engineered tomato plants was a threefold boost in the hydrophilic antioxidant capacity of the fruits. In an experiment this anthocyanin-containing tomato significantly extended the life span of cancer-susceptible mice that were fed with the new tomatoes compared to mice that were fed with normal tomatoes.

Paul Fraser from the Royal Holloway University London, UK, talked about the progress made in the genetic engineering of isoprenoids in solanaceous species, particularly in tomato. He explained different modifications of carotenoid biosynthesis in chloroplast and chromoplasts of tomato fruit [3]. Most interesting was the observation that the endogenous carotenoid pathways in higher plants seem not to react to engineered changes. Often this resistance appears in form of intrinsic regulatory mechanisms that are "silent" until manipulation of the pathway is initiated. These mechanisms may include feedback inhibition, metabolite channeling, and counteractive metabolic and cellular perturbations.

Molecular breeding of Medicinal Plants

Malaria is a severely life-threatening infectious disease which affects approximately half of the world's population with risk of infection. Only in the year 2008, 247 million cases of malaria occurred and nearly one million deaths were recorded. One of the most effective treatments for malaria is an artemisinin combination therapy (ACT). Artemisinin is the active compound of the plant Artemisia, grown in China, Vietnam and East Africa where it has been used for years to treat intestinal parasites. The World Health Organization lauds it as a safe malaria treatment candidate.

In this talk Ian Graham (CNAP Director & Weston Chair of Biochemical Genetics, University of York) presented his ongoing research, the CNAP Artemisia Research Project. This project is aimed to make use of the most recent developments in genetics, bioinformatics and analytical technologies to speed up the breeding of Artemisia annua. A series of specially-developed assays were used to screen several of Artemisia progenies rapidly and select the most promising ones for use in plant breeding. Plants were selected for desirable features like increased ratio of leaf to stem tissue, plant bushiness, delayed flowering, leaf size and shape. By use of the new genetic map plants were not just selected on the basis of observable features, but also according to their genotype profile. Subsequently, plants can be selected if they show positive QTL scores for key traits such as leaf area and artemisinin concentration. The CNAP project is well on track to produce molecularly bred high artemisinin yielding Artemisia varieties by 2012.

Containment strategies in Biopharming

Denis Murphy from the University of Glamorgan, UK (also Biotechnology Advisor to United Nations Food and Agriculture Organization), addressed the challenges of segregating biopharmed crops from mainstream crops, particularly those destined for food or feed use. Recently serious concerns have been raised in the scientific community and also in the public, regarding the usage of major food crops as platforms for production of pharmaceutical compounds. Great emphasis is required for the rigorous separation of food and non-food varieties of the same crop species via a range of either physical or biological methods. Denis Murphy stressed, that very effective methods for the bio-containment consist of the use of plastids for transgene expression, inducible and transient expression systems and also physical containment of plants or cell cultures [4]. Containment can be increased by the use of non-food crops, non-crop plants or in vitro cultures as production platforms instead of food crops. The use of non food crops is also very promising to obtain approval of the European Union (EU) for plant-based production of pharmaceuticals. Shifting the research focus from the major food crops as rice and maize to non-food crops will also contribute to achieve GMs acceptability. The speaker was optimistic about the EU approval of non food crops for Biopharming within the next decade. It was clear that in the current atmosphere of heightened concerns about food safety and biosecurity, the future of Biopharming will largely be determined by the extent to which the sector is able to maintain public confidence. It requires thoroughly considered approaches to address the issues of containment and to comply with the security regulations for GM crop production systems.

Conclusion

This was a reasonably well organized meeting which enabled efficient interaction and networking between the participants in the Biopharming area. The meeting addressed a wide spectrum of topics within molecular farming, ranging from recombinant protein expression to breeding of medicinal plants. Presentations covered numerous technological novelties along with valuable contributions on safety issues and containment strategies.

Acknowledgements

This meeting was organized by Euroscicon (www.euroscicon.com). The next Euroscicon meeting on Molecular Pharming will take place on the 20th September 2011- 'Molecular Pharming - recent progress in manufacturing medicines and plants' (www.regonline.co.uk/molecular2011).

Financial and competing interest disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

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