The next big expression chassis: microalgae and the future of biomanufacturing (part I)

Humans have a long history of swiftly evolving manufacturing processes to increase efficiency and make new valuable products available for those that need them. In this article, Nusqe Spanton, founder and CEO of Provectus Algae, outlines why microalgae are ready to take the stage as the next big class of expression chassis thanks to their wellspring of advantages and unique attributes.

Even within this context, it’s mesmerising to witness the meteoric rise of biomanufacturing. In just a handful of decades, scientific teams have gone from developing the principles of molecular and cell biology to using living systems to create valuable materials, therapeutics, food products and more.

Thanks to the rapid emergence of synthetic biology, a growing toolkit of genetic engineering methods and technological improvements, this growth has accelerated. These advancements have provided biotech companies and biomanufacturers with an increasing array of approaches to tap cellular systems to produce key biologic products at scale.

Despite this amazing progress and bona fide blockbuster biologic products, it’s clear that we are still only at the cusp of the biomanufacturing era. In part, this is because of the sheer volume of possible future biologic products that have not yet hit the market. Importantly, it’s also because researchers have not fully explored life on Earth.

Organisms we haven’t yet fully explored and characterised may have untapped potential as expression chassis. This begs the question: can bioprocess development become more efficient and effective by expanding this list of available expression chassis and tailoring their selection to specific molecules? Most researchers would agree with this sentiment; but, developing a diverse collection of cellular expression systems requires an investment of time and resources.

Biomanufacturers currently use several different cellular expression chassis classes to produce a wide range of biologic products. Historically, bacterial (E. coli), yeast (S. cerevisiae), insect (Sf9) and mammalian (CHO, HEK293, etc.) cells have been the most common in commercial bioprocesses, particularly for recombinant proteins.¹ Each chassis comes with different advantages and disadvantages that dictate the applications they are best suited for.

Even with well understood and popular cellular expression chassis, finding cost-effective, efficient and productive cell systems for bioprocesses is no small feat. This is particularly true for groups producing unique natural products/biomolecules, biologic products that are toxic to existing chassis, new biotherapeutic modalities, high value materials traditionally made synthetically and other complex materials.

Collectively, this has driven biotechnology and synthetic biology teams to work towards the rapid development of new expression chassis –– though many of these efforts still focus on the chassis classes listed above.

As biomanufacturing advances, so too will the number of cell and chassis types. So, what might the next big class of cellular expression chassis be? After some initial struggles, microalgae species are ready for wide adoption as cellular expression chassis … and their future as the next big class is much closer than you might think.²

What are microalgae?

Microalgae represent one of the oldest, largest and most diverse groups of organisms on our planet. As their name implies, they are microscopic, unicellular species that typically grow in freshwater and marine environments and span many different genera. In their approximately one to two billion years of existence, microalgae species have evolved to survive in nearly every ecosystem type on Earth, including some of the most uninhabitable.³

Through this conquest, microalgae diverged from one another to survive diverse environments with unique demands. Responding to differing light conditions, carbon dioxide (CO₂) concentrations, nutrient availability and environmental attributes, each microalgal species evolved specific genetic and biochemical characteristics.

This allows them to generate the wide range of molecules needed for survival in their distinct environments. Throughout many millennia and with many selective pressures, an impressive number of microalgae species cropped up, each with unique natural products and metabolic profiles.

Although the exact number of species is difficult to pin down, one conservative estimate places the number at around 70,000 species, whereas others range from 200,000 to several million.^3–5

Microalgae use in human society

Although humans have used microalgae species in their diets for hundreds of years, scientists didn’t start exploring microalgae biotechnology until the middle of the 20th century.^6.7 Through these investigations, researchers determined that microalgae could be applied as sustainable, photosynthetic expression chassis –– although they generally focused on a small subset of species. As a key early example, commercial groups in the 1980s cultured Dunaliella salina to make β-carotene, a nutritional ingredient that gets converted into vitamin A.⁷

The scientific community now recognises that microalgae species can produce many different high-value molecules, such as pigments, flavours, fragrances, growth factors, fatty acids, antioxidants, oligosaccharides, proteins, terpenes, amino acids, peptides and other materials for key industries.⁸ In fact, researchers have identified thousands of novel compounds in microalgae while also exploring their ability to produce recombinant biomolecules, including biopharmaceuticals.^9,10

Why use microalgae in biomanufacturing?

Clearly, microalgae are a rich potential source for high-value materials and biologics. However, microalgae chassis need to complement and compete with existing cellular expression chassis, such as CHO or E. coli cells. Indeed, microalgae offer a unique constellation of advantages that expand options for biomanufacturers and drive its adoption in bioprocesses.

A massive reservoir of species and metabolic diversity

The sheer scale of microalgae species and metabolic diversity offers tremendous potential to biomanufacturers.¹¹ With a greater number of starting points for cell selection and bioprocess development, biomanufacturers have more options to investigate when working to identify cells that maximise their efficiency and efficacy.

For a given target molecule, they can evaluate the characteristics of countless different microalgae species, screening for optimal cellular productivity, chemical compatibility and more. Additionally, biomanufacturers can tap into the existing profile of unique and valuable materials that microalgae species naturally make.

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Organisations can browse well-characterised microalgae species to find options that already express their target molecule or close precursors. By finding a species that naturally produces a key molecule, biomanufacturers can speed up their development and scale-up timelines.

Driven by previous decades microalgae research, biomanufacturers and key industries are already actualising the bioprocess potential of microalgae, applying them to generate high value products.¹² Discoveries of commercial value will only continue to accelerate as R&D efforts extensively examine more microalgae species, given that only a small number (approximately 15) are currently cultured at relevant commercial scales.

A cellular photosynthetic expression chassis: carbon sequestration and sustainability

Microalgae are photosynthesis powerhouses; they’re responsible for producing approximately 50% of the world’s oxygen, proportionally capturing CO₂ to do so.^13,14 Their use of photosynthesis for growth offers key “built-in” benefits when adopted as expression chassis, specifically when it comes to bioprocess sustainability.¹⁵

Unlike other cellular chassis, photosynthetic microalgae use light as their energy source and CO₂ as their primary feedstock, thereby sequestering carbon as a bioprocess by-product. This means that biomanufacturers can use microalgae as a carbon-negative expression chassis, fixing CO₂ to generate valuable materials and biologics.

The use of photosynthesis also reduces the need for nutrients, media ingredients and other raw materials that other cellular chassis need to function. This brings additional sustainability benefits as the production, storage and distribution of these raw materials can add to a biomanufacturer’s total carbon footprint.

Although some plant species have also been adopted as photosynthetic expression chassis, it’s critical to note that microalgae enjoy faster growth rates and fix CO₂ as much as 10–50 times faster than terrestrial plants, among other advantages.^16–18 In short, microalgae appear to have widespread applicability as photosynthetic expression chassis, for both economic and environmental reasons.

References

1. N.K. Tripathi and A. Shrivastava, “Recent Developments in Bioprocessing of Recombinant Proteins: Expression Hosts and Process Development,” Frontiers in Bioengineering and Biotechnology 7, 420 (2019).
2. www.labiotech.eu/in-depth/algae-biotechnology-market/.
3. J. Singh and R.C. Saxena, “Chapter 2: An Introduction to Microalgae: Diversity and Significance,” in Handbook of Marine Microalgae (Elsevier Inc., Amsterdam, the Netherlands, 2015): pp 11–24.
4. M.D. Guiry, “How Many Species of Algae Are There?” Journal of Phycology 48, 1057–1063 (2012).
5. T.A. Norton, et al., “Algal Biodiversity,” Phycologia 35, 308–326 (1996).
6. J.L. García, et al., “Microalgae, Old Sustainable Food and Fashion Nutraceuticals,” Microbial Biotechnology 10(5),1017–1024 (2017).
7. M.A. Borowitzka, “Algal Biotechnology,” in D. Sahoo and J. Seckbach (Eds.), The Algae World, Cellular Origin, Life in Extreme Habitats and Astrobiology 26, 319–338 (2015).
8. M.I. Khan, et al., “The Promising Future of Microalgae: Current Status, Challenges and Optimization of a Sustainable and Renewable Industry for Biofuels, Feed and Other Products,” Microb. Cell Fact. 17, 36 (2018).
9. K.H.M. Cardozo, et al., “Metabolites from Algae with Economical Impact,” Comp. Biochem. Physiol. Part C Toxicol. Pharmacol. 146(1–2), 60–78 (2007).
10. S. Rosales-Mendoza, et al., “The Potential of Algal Biotechnology to Produce Antiviral Compounds and Biopharmaceuticals,” Molecules 25, 4049 (2020).
11. www.technologynetworks.com/immunology/articles/speaking-algae-tapping-the-ancient-power-of-microalgae-using-synthetic-biology-351022.
12. V. Dolganyuk, et al., “Microalgae: A Promising Source of Valuable Bioproducts,” Biomolecules 10(8), 1153 (2020).
13. https://theconversation.com/inside-the-world-of-tiny-phytoplankton-microscopic-algae-that-provide-most-of-our-oxygen-159955.
14. M.J. Behrenfeld, “Climate-Mediated Dance of the Plankton,” Nature Clim. Change 4, 880–887 (2014).
15. https://pharmaceuticalmanufacturer.media/pharmaceutical-industry-insights/biopharma-news/can-photosynthesis-lead-to-more-sustainable-biomanufacturing/.
16. www.genengnews.com/topics/bioprocessing/plant-based-biopharmaceuticals-a-growing-trend/.
17. S. Fahad, et al., “Recent Developments in Therapeutic Protein Expression Technologies in Plants,” Biotechnology Letters 37, 265–279 (2015).
18. V. Bhola, et al., “Overview of the Potential of Microalgae for CO₂ Sequestration,” International Journal of Environmental Science and Technology 11, 2103–2118 (2014).

Part two is available here.