New scalable strategy for challenging plant-based medicines A European consortium working on the MIAMi project is using yeast to support sustainable, scalable production of complex chemical compounds in rare plants, to harness their valuable healthcare and pharmaceutical properties. We speak to Dr. Michael Krogh Jensen, Group Leader & Senior Researcher from the Technical University of Denmark. About half of modern medicines are plant-based and plants provide the ingredients of highly effective medicines for several debilitating and life-threatening conditions. For just a couple of examples to show the usefulness of plant-derived medicines, take the anti-malarial drug Artemisinin, from the sweet wormwood plant – it damages the malaria parasite in red blood cells, or the opium poppy, harbouring opiates for pain medicine and used in morphine. Plants are invaluable and can provide us with an enormous range of uses for healthcare. The MIAMi project focuses specifically on tropical plants possessing the molecules known as MIAs (monoterpenoid indole alkaloids), which are plant secondary metabolites. There are more than 2000 MIAs in nature, but they can be rare, so studying them is not always possible. This rarity also means it is near impossible to harvest them and furthermore, exploiting them could lead to their extinction. However, it is known they can be used for anti-cancer therapeutics, anti-psychotic drugs and anaesthetics so finding better methods to utilise them for treatments is an important goal in healthcare. The challenges of extracting MIAs “We have millions of species of plant on this planet, most of them full of interesting chemicals and apart from problems like habitat destruction, and the extinction of plants, even if we find interesting substances in a plant this does not mean we can directly use them, because if you use a substance you have to have it in sufficient amounts, you need to produce them cheaply and sustainably and that’s where we often find problems,” said Linus Naumann, from the Max-Planck Institute, who is working on MIAMi. “Some plants require you to harvest tonnes of them for milligrams of the substance. Some may grow extremely slowly. There may be some that you cannot cultivate at all because they need symbiotic interactions that only occur in their natural habitat. Many interesting plants are also very rare so they would become extinct if exploited. You can see the dilemma.”
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By machine learning-guided elucidation of biosynthetic pathways for monoterpenoid indole alkaloids found in plants, the EU-funded MIAMi consortium are refactoring alkaloid biosynthesis in yeast cells using computer-aided design tools, advanced genome engineering, mass-spectrometry-assisted imaging, and enzyme characterization to enable fermentation-based manufacturing of natural and new-to-nature alkaloids from engineered yeast cells. Lærke M.M. Lassen
As if this wasn’t enough to dissuade the exploitation of the plants, the process for extracting them can involve solvents and large amounts of energy which shows it’s not kind to the environment. Production of pharmaceutical ingredients can also be hindered when there are gaps in knowledge about biosynthetic pathways. “Sometimes, these molecules quickly become so complex and intricate that even our biochemists cannot efficiently reproduce them in the lab. Even in the year 2020, we rely on growing these plants and extracting the molecules.”
The chemical mastery of plants It may seem strange that modern science cannot keep pace with this natural manufacturing process but there are good reasons. Plants rely on chemicals for nearly
all of their interaction with their environment because plants cannot move from where their seed falls. They face threats such as being attacked by insects and eaten by larger grazing animals, they have to deal with extremes in weather and they must be attractive to pollinators to reproduce. Therefore, they rely on a specific, targeting, chemical production for each job, for defence, for attraction, even for signalling and conveying warnings of attack, to other plants. They have developed chemical mastery in nature and this specialism, honed over evolutionary time frames is beyond our abilities to mimic and reproduce them. The impracticalities and inefficiencies in the process from extraction to synthesis, mean that whilst the range of plant-derived pharmaceuticals is potentially vast, only a fraction can be used for medical treatments.
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