Reproducing plant-production processes for key drugs
Around one quarter of all prescribed pharmaceuticals in the developed world are derived from plants, including well-known drugs such as morphine and codeine. Harvesting plants to derive such medicines can be slow, wasteful and very expensive, yet often no synthetic alternative exists.
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However, recent developments have broken new ground in the race to synthesise such important drugs. The European Union (EU)-funded project SMARTCELL has been able to reproduce part of the production process that plants use to “manufacture” such medicinal compounds, and the project team has discovered and cracked the gene code for four new genes.
“About fifty percent of the pharmaceutical compounds in new drugs in the last thirty years have come from nature,” says project coordinator Kirsi-Marja Oksman of the VTT Technical Research Centre in Finland. “For anti-bacterial compounds the percentage is even higher – around seventy percent. And the exact mechanisms that plants or microbes use to produce these compounds are understood very little.”
SMARTCELL team aimed to reproduce the process by which plants themselves manufacture such valuable chemical compounds, using cultivated plants or plant cells – hence the name of the project. “Different research teams across Europe have all made discoveries of parts of the process,” she says. “We wanted to bring that information together and develop the biotechnological tools that chemists and researchers can use to duplicate the production process that occurs inside the plant itself.”
The project researchers developed a number of tools that are able to exploit the secondary metabolic pathways within plant cells - how they actually manufacture certain chemical compounds within the plant. The team was also able to demonstrate proof-of-concept by achieving large-scale production of a key target compound. Such achievements are critical to effective volume production of pharmaceutically valuable products.
SMARTCELL team focused on what are called terpenes, one of the largest groups of these compounds, which are produced by a wide variety of plants (particularly conifers). Terpenoid products are used for a variety of applications in pharmaceuticals, natural pesticides, scents and flavours.
One plant in particular, the medicinal plant Catharanthus roseus or the Madagascar periwinkle, played a central role in the project. The plant synthesises over 150 different terpene-derived compounds. The most important of these compounds are the pharmaceutically relevant vinblastine and vincristine, medicinal compounds that are crucial in the development of anti-cancer drugs. Both are used in the treatment of leukaemia, and they are the main reason why children with the disease often now survive rather than succumbing to its effects.
Catharanthus roseus is the sole source of these two commercial anti-cancer compounds. Yet to produce vincristine, for example, by means of simple harvesting requires some 500 kg of the plant in order to produce one gram of the compound, which is why these drugs are so valuable.
“We can now understand the plant-production process – the green pathway, if you like – approximately halfway to the production of vincristine,” explains Oksman. “In doing so we have discovered four new genes that play a vital role in the internal plant process. We are now able to manufacture an intermediate product – secologanin –in the lab, and have validated the role of the genes discovered in its pathway.”
It is hard to overstate the importance of these discoveries. Establishing the basis for the biotechnical production of such compounds is of key significance for the production of anti-cancer drugs. “We have obtained the genome sequence of Catharanthus roseus and developed the ability to put multiple genes at the same time into the plant cell which facilitates the process. Plants make use of some twenty to thirty genes to manufacture the compounds that we are interested in,” says Oksman.
“That is not to say that the SMARTCELL team can do the same with every plant,” she comments. “However, we have developed the tools that will be essential when studying the production of high-value compounds in other plant cell systems,” she concludes.