Great future ahead with the help of Plant Molecular Farming!

by Anneli Ritala and Suvi T. Häkkinen

Green

Roughly a year ago, we wrote a commentary “Molecular pharming in plants and plant cell cultures – a great future ahead?” to Pharmaceutical Bioprocessing [1]. And now a huge breakthrough has been made with the help of Plant Molecular Pharming: Two Ebola patients were saved with a plant-made antibody that is still in the experimental phase.

Pharming or Farming?

The term Molecular Pharming is used to highlight the production of protein-based biopharmaceuticals, which contribute to the sustainable production of drugs that promote human and animal wellbeing. It also applies to the production of valuable secondary metabolites such as the analgesic drug morphine and the anticancer drugs paclitaxel, vincristine and vinblastine which are far too complex molecules to be synthetized in an economically feasible way.

In broader perspective, term Molecular Farming can be used in the context of utilization of the versatility of plants and plant cells to produce diverse valuable proteins and other compounds for any applications. Thus Molecular Farming covers also other fields than pharmaceuticals and describes better the approach taken at VTT Ltd.

Biopharmaceuticals

Biopharmaceuticals are on the commercial forefront of the pharmaceutical sector and roughly 30% of the new drugs under development belong to this class. The biopharmaceutical market has been steadily rising and reached total cumulative sales of US$ 140 billion in 2013 [2].

The FDA (The US Food and Drug Administration) and EMA (The European Medicines Agency) are already familiar with the two major biopharmaceutical production systems:

  • Microbes – mainly Escherichia coli and different yeast hosts
  • Mammalian cells such as the Chinese hamster ovary (CHO) platform,

and standard protocols can be followed to ensure the approval of new products.

Currently, the equivalent protocols are emerging for plant-based production systems, and there is one plant-derived biopharmaceutical protein on the market: Elelyso™ (taliglucerase alfa). It is produced in carrot cells by the Israeli company Protalix Biotherapeutics and licensed to Pfizer Inc., and is used for the treatment of the life-threatening lysosomal storage disorder, Gaucher’s disease. The recombinant product gained FDA approval in 2012 and the product is currently for sale in USA and Israel.

Advantages of plant-based production systems

Picture2The plant-based systems are starting to compete with the above mentioned established biopharmaceutical production systems, and on a technological basis plant-based systems have the advantage in following areas:

 

  • Speed
  • Scalability
  • Improved product quality

In need-for-speed situations, like in case of epidemic diseases as Ebola and bioterrorist threats, the transient plant expression systems benefit from the rapid onset of recombinant protein production. The plant material is propagated before the introduction of foreign DNA, allowing plants to be grown in the open or in greenhouse conditions after which the plant material is moved into contained, GMP-compliant facilities for protein production.

The greatest advantage of intact plants that are stably transformed to produce a target protein is their unparalleled scalability. For biopharmaceutical products, manufacturing will probably be restricted to greenhouses and other closed environments to ensure product safety and batch-to-batch consistency when production is carried out under controlled conditions. The Canadian company SemBioSys developed a safflower-based production system for insulin before filing for bankruptcy in 2012. The SemBioSys platform was so outstandingly efficient that theoretically 16 mid-sized Canadian farms could have produced enough insulin to meet the entire exponentially growing global demand. At VTT we have taken an initiative in producing food allergen specific antibodies for diagnostic and safety verification purposes. The barley-produced antibody can recognize and precipitate beta-lactoglobulin, which is the major allergen in cow´s milk. The established platform has potential in development of hypoallergenic products for milk allergic patients [3].

The high product quality is gained with the use of plant cell suspension cultures for Molecular Pharming as well as Farming purposes. At VTT we have harnessed the traditional microbial bioreactors to cultivate plant cells at the 600-litre scale [3]. We are currently working on a pharmaceutical target, Transferrin, in a project getting financial support from the Academy of Finland. We also only recently got funding from ERA-Anihwa, and we are entering with our plant cell culture expression system on fish vaccine production which is a very relevant target for Plant Molecular Pharming . The annual loss in aquaculture caused by viral diseases is remarkable and in order to be able to keep the fast-growing aquaculture industry ecologically, environmentally and ethically sustainable, good health for farmed aquaculture organisms is essential.

Plant Molecular Farming provides a safe and sustainable platform for the production of valuable proteins and other compounds – the great future is here and we are happy to be part of it!

References

  1. Ritala A, Häkkinen ST, Schillberg S. 2014. Molecular pharming in plants and plant cell cultures: a great future ahead? Pharm. Bioprocess. 2:223-226.
  2. Walsh G. 2014. Biopharmaceutical benchmarks 2014. Nat. Biotechnol. 32:992-1000.
  3. Ritala A, Leelavathi S, Oksman-Caldentey KM, Reddy VS, Laukkanen ML. 2014. Recombinant barley-produced antibody for detection and immunoprecipitation of the major bovine milk allergen, ß-lactoglobulin. Transgen. Res. 23:477-487.
  4. Reuter LJ, Bailey MJ, Joensuu JJ, Ritala A. 2014. Scale-up of hydrophobin-assisted recombinant protein production in tobacco BY-2 suspension cells. Plant Biotech. J. 12:402-410.

AnneliThe author Dr. Anneli Ritala, Principal Scientist (PhD Pharm., Docent in Pharmaceutical Biology) has special expertise in production of recombinant proteins and small molecules in plant cell cultures. She has over 20 years´ experience on plant biotechnology, especially genetic and metabolic engineering of plants and plant cell cultures including barley, oats, tobacco and other medicinal plants. anneli.ritala@vtt.fi

SuviThe author Dr. Suvi T. Häkkinen, Senior Scientist (D.Sc.(Tech)) has special expertise in medicinal plants and natural compound research. She obtained her doctoral degree for her work related to alkaloid biosynthesis and she has over 15 years´ experience on plant biotechnology including metabolic engineering, recombinant protein production and plant cell culture technology. suvi.hakkinen@vtt.fi

 

 

Natural beauty preserved in plant cells

by Liisa Nohynek

VTT

Although the darkest time of the year is already behind us in Finland, it is still a long way to summer. At this time of year Nature´s colour palette consists mainly of different shades of grey. However, we at VTT have preserved our Finnish natural plants as plant cell cultures, which delight us with their colours all year round.

Berry plant cell cultures originating from plants that grew under the midnight sun last summer are now glowing in our culturing rooms with bright colours: yellow and different shades of red, pink and purple. The flavour of our bilberry cell culture reminds us of fresh berries.

The colourful cultures do not exist only for our own joy, but are created to be used in a wide variety of applications, particularly cosmetics. Plants and their extracts are the source of a huge variety of chemicals, and have been used for promoting skin health and beauty since ancient times.

Some of the leading global cosmetic companies have recently launched products with biotechnologically produced plant cells for novel applications exploiting the rich variety of plant-derived chemicals. This activity ensues from general global trends followed by the beauty business, such as the demand for natural, ecological and chemically safe products while exploiting the latest technological methods and tools. The use of plant cell cultures instead of entire plants in cosmetic products follows these trends, and helps protect endangered natural plant species from overexploitation.

Arctic bramble, crowberry and cloudberry

We have joined in the front line of this research area and are maintaining a strong infrastructure and knowhow on plant cell culture technology. Our special interest is in Nordic plants, such as arctic bramble (Rubus arcticus), crowberry (Empetrum nigrum) and cloudberry (Rubus chamaemorus).

We cover the whole field of biotechnological processes, starting from establishment of plant cell cultures from pieces of natural plants and ending up in industrial scale production protocols for plant cells. Cultured plant cells are totipotent having the capacity to develop into any organ of the plant. However, when treated with plant growth regulators the cells multiply continuously, producing biomass consisting of identical, undifferentiated cells. In addition to the ecological advantages of this technology, the industry avoids the significant problem of plant raw material availability. The cell cultures can be sustainably generated all year round with consistent chemical quality, and production of chemically and microbiologically safe plant-based material can be ensured.

Specific cocktails of compounds in Nordic plants

The natural conditions in Northern Scandinavia are harsh, and therefore demand special properties of plant species in order for them to survive the long, cold winter and to grow and breed during the summer. A thousand years of adaptation to the short, fickle Nordic summers full of light has resulted in the development of plants with a specific cocktail of compounds protecting them from abundant UV-light, cold nights, insect and microbe attacks, and wet snow in the middle of the summer season. The genotypically expressed desired chemical compounds present in natural plants can be generated in their cell cultures.

Selected plant cell cultures contain nutritionally valuable compounds, such as omega-3 and omega-6 fatty acids, flavours and pigments, and may exhibit antimicrobial and antioxidant activities with special relevance for human skin health and beauty. For example the purple to dark-red coloured anthocyanins protecting bilberry skins against UV–light and harmful microbes have a potentially similar effect on human skin.

The chemical composition of plant cell cultures is still only partially explored

Novel bioactive compounds are continuously searched by cosmetic companies for skin care and make-up products. Plant cell culture technology, including the cultivation of less well-known plant species as well as modification of plant cell cultures with elicitors and precursors, also has the potential to respond to this need – even in the middle of the dark and freezing Nordic winter.

Liisa NohynekThe author Dr. Liisa Nohynek, Senior Research Scientist, PhD in microbiology, has special expertise in plant cell culture technology. She has extensive experience on plant bioactive compounds, especially in Nordic berries and berry cell cultures. She is also experienced in scaling-up processes enabling production of plant cell biomass with bioactivities for industrial applications. liisa.nohynek@vtt.fi