White paper: How synthetic biology can help decarbonise pharmaceuticals

The pharmaceutical industry is significantly more carbon intensive than many other industries, such as automobile manufacturing [1]. Furthermore, with pharmaceuticals representing approximately 25% of the carbon emissions associated with the NHS [2], medicines provide an excellent opportunity for carbon reduction. The chemical synthesis of medicines often requires expensive reagents, catalysts with a high embodied carbon content or low relative abundance (e.g., precious metals and rare earths) and high temperatures/pressures, all necessitating high consumption of energy, therefore producing a lot of carbon. Biological processes, however, require lower temperatures (often 37 ?C) and removes the need for expensive and unsustainable catalysts. Bioreactors are already used to make products such as insulin, however, many medicines have complex synthesis pathways, and are not currently found in nature. Synthetic biology provides the molecular toolkit to build up modular biochemical pathways, insert them into host organisms to generate chemical compounds through biosynthesis. Once a biochemical pathway is complete within a host organism (for example E. coli), the desired product can be made biologically. Furthermore, biosynthetic pathways can use renewable feedstocks in place of fossil fuel feedstocks, and even sequester carbon when using photosynthetic organisms. This article explores how medicines can be made using biosynthesis, how synthetic biology enables more medicines to be made through biosynthesis, and how this can all be achieved with an exceptionally low carbon footprint.

Biosynthesis – How can Microbes make Medicines?

Biosynthesis is the creation of a substance using biological pathways. This can be done through living organisms of any Kingdom. Plants are known to create medicinal products, for example salicylic acid (a similar compound to aspirin) can be found in the bark of a willow tree. Penicillin was famously discovered by Alexander Fleming from yeast left on a Petri dish and is now produced commercially using the fungi Penicillium chrysogenum. The biosynthesis of penicillin requires the three amino acids: L-adipic acid, L-cysteine and D-valine. These three amino acids undergo an enzyme catalysed condensation reaction to join them together. Isopenecillin N synthase creates the beta lactam ring, and the final step is an enzyme catalysed transamidation. All these steps are enzyme catalysed and can happen at room temperature with simple sugar-based feedstocks, and with a lower activation energy than chemical routes. Enzymes are protein-based catalysts which change the local chemical environment, making it conducive for reactions with high energy barriers or slow kinetics to be occur in a lower energy environment.

Widening Access to the Anti-Malaria Drug Artemisinin

A key development for medicines manufactured using synthetic biology techniques is the semi-synthetic production of artemisinin, a highly effective anti-malaria drug [3]. The plant-derived version suffered from producing very low quantities with low yields, therefore, the supply of artemisinin was blighted by shortages and price fluctuations [4]. Paddon et al. were able to develop a strain of Saccharomyces cerevisiae (baker’s yeast) to increase yield of artemisinic acid from 1.6 gl-1 to 25.0 gl-1. The authors achieved this through the discovery of a plant dehydrogenase enzyme, a second cytochrome, and integration into the genetic makeup of S. cerevisiae. The researchers waved intellectual property rights to maximise the impact of this development. Although the motivators behind this project were focused on widening access to medicines, the same molecular engineering tools can be used to develop low cost, low embodied-carbon medicines.

Feedstocks – Carbon Neutral Medicines by Design

Waste plant matter in the form of lignocellulose is available in abundance, is renewable and is already used within a wide range of commercial applications [5]. The lignocellulosic content will greatly reduce the emission factor of the end product, as carbon dioxide is absorbed from the atmosphere to create the product and associated biomass. Once the biochemical pathways to degrade lignocellulose into simple sugars is established and inserted into a host organism (for example introduced into E. coli via a plasmid), then the genes which encode the enzymes for the synthesis of the compound of interest can be introduced. Once the mutant organism with the desired biochemical pathway is established, cultivation within a bioreactor can create specialist compounds at scale. Combining biosynthesis with traditional pharmaceutical procedures will allow for efficient, low energy and low carbon manufacture.

Photosynthetic organisms such as the duckweed algae can also be used to create specialist compounds [6]. During their lifecycle, photoautotrophs incorporate CO₂ into their biomass and the compounds they produce. If carbon is locked away into pharmaceutical compounds during biosynthesis, and all subsequent steps are carbon neutral, then carbon neutral pharmaceuticals could become a reality. Furthermore, if a co-product which stores carbon (such as building materials) is generated in parallel, the whole process could even be carbon negative [7].

Challenges and Barriers

Given the possibility of carbon negative medicines, when will healthcare workers be able to prescribe carbon negative medicines? Unfortunately, there routes of biosynthesis of most pharmaceuticals are currently unknown, however, researchers are making remarkable progress. Each product will have a complex biosynthesis pathway, each step involving unique biomolecules. Researchers need the genetic code, the tools to insert that code into a suitable host and ensure adequate expression. These inserted genes also need to avoid host mechanisms for destroying foreign DNA. Furthermore, the complete biosynthetic pathway may not already exist, highlighting the need to develop the library of molecular tools, as the researchers did for the anti-malaria drug artemisinin. However, the more molecular tools we uncover, the greater range of products can be produced biologically.

Conclusion

Biosynthesis is a potential low carbon alternative to the chemical synthesis of pharmaceuticals, even offering the possibility of carbon negative medicines. The anti-malaria drug artemisinin is a good example of how molecular biology tools can unlock biosynthetic routes to medicine production. Researchers have focused on developing new drugs, and rightly so. However, with the cost of carbon ever increasing, researching biosynthetic pathways for medicines with high embodied carbon may prove to be more cost-effective than other carbon reduction schemes, especially given the high impact of pharmaceuticals. 

1. References

[1] L. Belkhir and A. Elmeligi, “Carbon footprint of the global pharmaceutical industry and relative impact of its major players,” J Clean Prod, vol. 214, pp. 185–194, Mar. 2019, doi: 10.1016/J.JCLEPRO.2018.11.204. 

[2] S. Pfleger, “Pharmacy’s Role in Climate Action and Sustainable Healthcare,” The Royal Pharmaceutical Society, 2022. 

[3] C. J. Paddon et al., “High-level semi-synthetic production of the potent antimalarial artemisinin,” Nature, vol. 496, no. 7446, pp. 528–532, Apr. 2013, doi: 10.1038/nature12051.

[4] N. K. B. K. Ikram and H. T. Simonsen, “A Review of Biotechnological Artemisinin Production in Plants,” Front Plant Sci, vol. 8, Nov. 2017, doi: 10.3389/fpls.2017.01966.

[5] A. Gil, “Current insights into lignocellulose related waste valorization,” Chemical Engineering Journal Advances, vol. 8, Nov. 2021, doi: 10.1016/j.ceja.2021.100186. 

[6] N. E. Coughlan et al., “Duckweed bioreactors: Challenges and opportunities for large-scale indoor cultivation of Lemnaceae,” J Clean Prod, vol. 336, p. 130285, Feb. 2022, doi: 10.1016/j.jclepro.2021.130285.

[7] I. M. Goodchild-Michelman, G. M. Church, M. G. Schubert, and T.-C. Tang, “Light and carbon: Synthetic biology toward new cyanobacteria-based living biomaterials,” Mater Today Bio, vol. 19, p. 100583, Apr. 2023, doi: 10.1016/j.mtbio.2023.100583.