“ Plants are nature’s alchemists (….)”
The above quote from Michael Pollan reflects the complex chemistry that exists in the plant world. Plants live in the same spot their entire lives, from where they collect nutrients from the soil, CO2 from the air and energy from the sun, to make highly complex chemical compounds. Plant chemicals impact our lives in many ways. They include bioactive molecules important in nutrition and also compounds that became medicines against cancer; compounds with flavour like menthol, many scents that are used widely in various industries, and many more. The processes plants use (metabolic pathways) leading to many of these plant compounds are complex and only a few are completely understood.
Humanity has been harnessing this bio(chemical) potential, historically by using the plants themselves as a source of these molecules. There are several aspects that make this practice inconvenient and unsustainable for scaling access to the desired compounds. Using field-produced plants may be impractical at industrial scale, as yields are variable in field-grown plants and the compounds of interest may be naturally present in very small quantities only. Plants need them to repel pests, for example, and very minute quantities serve this purpose in the plant.
Alternative strategies to using the natural plant sources have thus been employed. Broadly, there have been two approaches:
1) work with the plants or plant-derived material with the goal of increasing the availability of the chemicals of interest,
2) try to replicate the plant chemistry (by using synthetic chemistry) and biochemistry (metabolic engineering and synthetic biology) outside the native plants.
Breeding for higher yield plants has focused on compounds important for nutrition, while other strategies have been used to access the chemical complexity of the plant secondary metabolites and to increase the amounts produced.
Plant cell culture can allow for broader manipulation of the conditions that favour synthesis of compounds of medical interest. Phyton Biotech and Alternative Plants are examples of companies that are developing such techniques. Ayana Bio is a spin off of Ginkgo Bioworks, the synthetic biology platform company, that will use its plant cell culture technology to produce bioactives important in nutraceuticals and in herbal medicine.
Often, plants developed specialized structures (organs and tissues) to accumulate and/or secrete the compounds, which are not possible to reproduce in a plant cell system. Plant cell culture conditions that potentiate synthesis of the complex molecules may not always be possible to create in laboratory conditions, a limitation in this approach.
Use of synthetic chemistry: once the compound of interest has been chemically identified, a search for synthetic production pathways starts. As an example, today the larger proportion of the more than 34 000 metric tons per year of menthol used is made using a synthetic chemistry route (see here).
Sometimes, the molecules of interest are so complex that it has not been possible to develop a suitable synthetic chemistry route. For example, the Madagascar periwinkle-derived vinca alkaloids that are used in cancer treatments, have been produced using full chemical synthesis, but industrially, the plant material is still used, despite the very low natural yields. Another example is artemisinin, the antimalarial compound produced by Artemisia annua: chemical synthesis was achieved but the process and yields are not compatible with industrialization. Semi-synthetic pathways have also been developed but there is vast room for improvement.
Biotechnology tools such as metabolic engineering have been continuously improving. Over the past 15 years, the metabolic engineering of industrial production microbes allowed successful production of many compounds of plant origin (see here). Corporations such as Amyris, Manus Bio, Octarine Bio, have made important advances using synthetic biology to enable production of complex plant-origin metabolites in industrial microorganisms. Academic and private research teams are making important advances in building microbial strains that can produce these types of important compounds with relevant yields (see for example a recent publication about production of the cancer drug vinblastine in engineered yeast here).
A novel approach (see here) to increasing the natural yields in plants that combines pathway engineering and improved agro-infiltration, enabled a research team to produce gram-scale quantities of purified triterpene (one of the groups of complex secondary metabolites with high industrial interest) in N. benthamiana plants, in just a few weeks. It will be exciting to continue to follow this type of alternative approach in their path to industrialisation and commercialisation.
While the process of unravelling the way plants produce these complex molecules has been long and laborious –
”Keasling estimates that it has taken roughly 150 person-years of work including uncovering genes involved in the pathway and developing or refining parts to control their expression (to produce artemisinin in a microbe)”
– interest in plant-derived compounds is again increasing and there are reasons for optimism about our ability to find means of producing important compounds in a sustainable manner. Science, technology and the current societal and economic contexts are converging towards delivering improved solutions for sustainable industrial production of plant-derived complex compounds.