Time To Shine: Photosynthetic Biotech Is Ripe for the Picking

The biotechnology industry is largely an enterprise based on a small sampling of life. Biotechnologies and biomanufacturing are dominated by a few bacterial, fungal and animal cell systems. Taking away Escherichia coli, Bacillus subtilis, Saccharomyces cerevisiae, Aspergillus niger, Trichoderma, HEK293 and CHO cells, what remains of the industry? While these cells will continue to be important, it’s likely that we will miss opportunities if we focus efforts too narrowly.

Though present in the agricultural industry, photosynthetic biotechnologies are perhaps the most glaring deficiency in the life science sector. This is a bit ironic given that Gregor Mendel’s foundational 19th-century genetic inheritance studies relied on pea plants.

While wider application of photosynthetic biotechnologies has lagged behind, we expect that recent advancements and industrial attention will drive significant commercial strides in the coming decade. Renewed efforts to tap cyanobacteria, algae and plants in arenas typically dominated by heterotrophic systems are already beginning to yield fruit.

To prepare for biotechnology’s green epoch, let’s discuss the inherent value of photosynthetic biotechnologies and address their challenges, highlighting some exciting enterprises in our community along the way.

Why bother with photosynthetic biotechnologies?

The diversification of available biological tools isn’t done in a vacuum. It must be done to solve challenges and create new value.

The carbon capture experts

To that end, widespread photosynthetic biotechnologies can help solve one of the most pressing challenges of the life sciences sector: its carbon emissions.

Biotech and biopharma already contribute significantly to the planet’s global carbon footprint. To put this into perspective, a recent report estimated that the global biotechnology and pharmaceutical industries produce ~260 million metric tonnes of CO₂ equivalent annually, more than the paper and forestry industries combined. Separate from carbon released from energy use, packaging, operations and shipping, most cell systems used to make bio-based chemical and biological products naturally produce CO₂. As the biomanufacturing industry continues to grow, so will the number of cells producing CO₂.

Photosynthetic systems instead offer a mechanism to consume CO₂ to generate valuable ingredients and bioproducts. Through the adoption of photosynthetic systems, companies can eliminate a large source of carbon emissions and replace it with bioprocesses that use CO₂ as a feedstock, instead of sugars and costly nutrient mixes. Given the many life science companies aiming to reach net zero emissions, the adoption of photosynthetic biotech is a pragmatic and economical solution.

Algae technician inspects green microalgae culture. Credit: Provectus Algae

Going further, the ability of photosynthetic biotechnologies to fix carbon can also be used across other sectors. For instance, Prometheus Materials developed a proprietary biotechnology that uses a cement-like bonding substance from microalgae to produce bio-based concrete bricks. Prometheus aims to use its tech to curb cement’s massive carbon footprint, which amounts to ~8% of global emissions.

Harvesting valuable metabolite diversity

Photosynthetic organisms also provide a massive pool of unique biochemicals and metabolites. Plants and algae are Earth’s original chemists, capable of making a wide range of compounds for survival. Many natural products made by photosynthetic organisms have innate potential in society. Case in point: the discovery of salicylates in long-used medicinal plant species led to the development of aspirin (acetylsalicylic acid), which played a tremendous role in the rise of the pharmaceutical industry. Without early botanical research, the pharmaceutical industry would not exist as we know it today. Though natural product research in photosynthetic organisms is well appreciated in drug discovery, its application spans functional cosmetics, foods, beverages and beyond.

The continued rapid acceleration of multiomics analysis and AI have made the discovery of bioactive molecules in these organisms easier. In turn, some companies are actively exploring naturally occurring metabolites from photosynthetic organisms. As an example, Brightseed uses its Forager^® system to understand the metabolomic diversity of plant species for the discovery of molecular products for food and consumer health industries.

Producing recombinant gene products

Photosynthetic organisms also provide opportunities for manufacturing recombinant gene products. The addition of photosynthetic biomanufacturing chassis would expand the options available to life science companies looking to express novel biomolecules, offering a unique constellation of advantages that complement traditional systems.

For example, most photosynthetic organisms contain the cellular machinery needed to properly fold complex eukaryotic proteins. In addition, photosynthetic cells are not susceptible to human pathogens in the same way that many common mammalian cell systems are. Thus, the adoption of photosynthetic bioprocesses offers a mechanism to produce properly folded proteins while simultaneously lowering contamination risks associated with human pathogens found in mammalian cell culture (including mycoplasma and viruses like herpes, adenoviruses and parainfluenza). Photosynthetic bioproducts and bioprocesses are also generally “animal origin free.” This provides manufacturers with significant safety advantages and reduced regulatory risk, while also appealing to animal-conscious consumers.

Some biopharma companies have already adopted plant biomanufacturing. Pfizer’s Gaucher disease drug, Elelyso^® (a recombinant glucocerebrosidase), was the first FDA-approved drug made in plant cells back in 2012. Going further, plant-based vaccines have become a point of emphasis for the industry. Last year, Medicago’s tobacco-grown COVID-19 vaccine was shown to be effective in preventing COVID-19 across multiple variants. Even more recently, Evonik launched an amaranth oil-derived squalene (PhytoSquene^®) for use in adjuvants as an alternative to animal squalene, typically sourced from shark liver oil.

Photosynthetic biotechnologies can even serve as drug-delivery mechanisms. For instance, researchers have explored the use of microalgae cells for delivering drug payloads. Notably, Lumen Bioscience is actively exploring the clinical utility of spirulina-based oral delivery of recombinant protein therapeutics.

Overcoming persistent challenges to photosynthetic biotechnologies and biomanufacturing

If photosynthetic biotech holds such promise, why have broader applications in life sciences lagged behind until now? It comes down to less developed research infrastructure and their basic biology.

Closing the infrastructure gap with complete photosynthetic platforms

The primary hurdle to photosynthetic biotechnologies gaining broader appeal is that they are generally less studied and explored. A lot less resources have been devoted to comprehending both natural and heterologous gene expression in photosynthetic organisms and developing efficient genetic engineering approaches to better control their commercial applications.

Molecular biologist reviewing cell growth on a culture plate. Credit: Provectus Algae

Originally, molecular researchers identified and studied E. coli because of its status as a human pathogen. Ultimately, this research helped identify E. coli as a particular hardy bacterial species with utility as a biological tool. Similarly, researchers studied S. cerevisiae’s applications because of its long history in baking and brewing. In both cases, researchers took on additional activities using these organisms because there was a significant body of work already available to build upon. Once more tools came online for these systems, it further entrenched their use in biotech and biomanufacturing. A classic case of the rich getting richer.

To solve this challenge, some companies are opting to build that infrastructure for their photosynthetic systems of choice, supplying core technologies to their partners. By providing a complete platform, these organizations can help others identify, develop and commercialize products from photosynthetic systems. For example, Phylloceuticals specializes in making protein therapeutics using genetically modified plants through its Phytopharma as a Sustainable Technology (PhAAST™) platform. Using either tobacco or duckweed (Lemna spp.) bioproduction formats, the PhAAST platform helps drive pharmaceutical manufacturing and commercialization by covering technological gaps from vector optimization and product development to regulatory strategy and manufacturing automation. Similarly, our microalgae biomanufacturing platform aims to solve past challenges of large-scale microalgae bioproduction by supplying partners with the critical technological infrastructure needed to bring a microalgae bioproduct to market.

Addressing basic biology complexities with new genetic tools

A lot of commercial enterprises either avoided or struggled with applying photosynthetic organisms because of their basic biology. For one, arable land requirements and slow growth rates of many photosynthetic organisms hampered their industrial applications. However, the use of new cultivation approaches, more efficient strains and bioprocesses using fast-growing aquacultural species, like microalgae and duckweed circumvent these issues.

Additionally, cell walls often make transformation and genetic engineering strategies more challenging. It’s also more common for photosynthetic organisms to be polyploids. Greater redundancy in photosynthetic genomes can complicate the creation of genetic knock-outs.

As a result, photosynthetic organisms have been more historically difficult to genetically engineer in a precise manner. For decades, researchers lacked tools to perform site-specific genetic engineering in photosynthetic cells. The primary historical method for genetic engineering in plants makes use of agrobacterium, which randomly inserts DNA segments into nuclear genomes. Though agrobacterium transformation made adding recombinant genes into photosynthetic cells possible, its lack of specificity often necessitates significant screening efforts to ensure constructs can effectively produce target proteins. It is also limited to a specific host range.

More recently, other approaches for photosynthetic cell transformations have been developed and explored in plants and algae. Particle bombardment (or biolistics) has become an important strategy for photosynthetic organisms because of its wide host range and high DNA incorporation efficiency. Particle bombardment is also particularly useful for engineering plastids with recombinant genetic information.

In addition, the advent of CRISPR systems has opened the door to more sophisticated targeted genetic engineering in photosynthetic organisms for both agricultural and biotechnological applications. As an interesting use case, Pairwise adopted CRISPR technologies to create plant foods with greater consumer appeal and increased nutritional properties, including seedless berries, pitless cherries and nutrient-rich salad greens.

Navigating complex genetic regulation and gene silencing

Due to their environmental niches, ploidy and relationship with light, photosynthetic organisms developed mechanisms for tightly controlling their gene expression. In particular, many photosynthetic organisms evolved powerful gene silencing mechanisms, especially for mitigating foreign pathogenic genetic information. As a result, transgenes are often silenced in both plants and algae, resulting in low expression.

Through the growth of bioinformatics and machine learning, researchers have increased their ability to predict and understand gene function and regulation. Increasingly, researchers are able to better understand triggers for silencing and identify signaling pathways that lead to target gene expression. This information can be applied to rationally design promoters and vectors that tap into innate mechanisms to increase target expression for both natural and transgenes.

While a number of applications can be envisioned, the Big Purple Tomato represents one eye-catching illustration. By transforming indigo rose tomatoes with transcription factors from snapdragon plants, researchers were able to activate latent anthocyanin-producing genes normally silenced in the tomato fruit. As a result, Norfolk Plant Sciences produces tomatoes enriched for these antioxidants, offering consumers both health benefits and extended shelf-life. Having received US FDA approval in 2022, consumers can soon expect these proudly purple tomatoes in their grocery stores.

Additionally, we now know that silencing mechanisms are not present in the chloroplast. Thus, chloroplast engineering represents another key method for expressing transgenes without needing to contend with epigenetic silencing.

Photobioreactor illuminates modular biomanufacturing space. Credit: Provectus Algae

It’s also become clear that light conditions are deeply connected to genetic regulation. Since these organisms depend on light to produce the materials they need for survival, plants and algae have highly tuned mechanisms for adjusting to changing environmental conditions. Thus, to capitalize on the metabolic and biomanufacturing potential of photosynthetic organisms, researchers need tools that can help decipher the impact of lighting conditions on gene expression and manufacturing productivity. In fact, our Precision Photosynthesis™ technology makes use of highly controlled light systems and integrated feedback mechanisms to optimize microalgae light recipes for both biomass and target product expression.

Room to grow

No longer relegated to agriculture, photosynthetic biotechnologies offer life science companies new mechanisms to create ground-breaking AND sustainable goods. While the pharmaceutical sector is the most obvious place for photosynthetic biotech to establish deeper roots, there is increasing demand for bio-based alternatives to petroleum-reliant goods across cosmetics, food and beverage ingredients, specialty chemicals and bulk commodities. Exemplifying this shift, Givaudan, one of the world’s largest fragrance and cosmetic ingredients companies, recently acquired certain cosmetic ingredients from Amyris, including Neossance^® Hemisqualane, a plant-based silicone alternative.

Simply put, the existing heterotrophic biomanufacturing systems simply can’t meet all of this demand, especially in the context of expensive feedstocks and carbon intensive bioprocesses. That said, it’s on us in the industrial photosynthetic biotech community to keep working on making these technologies cost-effective and technically accessible. Companies developing photosynthetic biotechnologies must continue to lower the barrier to entry for the broader life science sector.

In doing so, more enterprises will opt to assimilate photosynthesis into their work. We anticipate that photosynthetic biotech will further blossom, ultimately meeting the measure of bacterial, fungal and mammalian systems known the world over.

About the authors

Chris Fisher, PhD – Chris Fisher is a chemical biologist and scientific communicator who passionately advocates for life science's vital place in society. Currently, he leads scientific affairs for Provectus Algae, a biotechnology company developing photosynthetic bioprocesses and biomanufacturing technologies for large-scale production of critical chemicals and biologics. Chris specializes in conveying scientific information to both internal and external stakeholders at all levels of expertise to better serve the needs of the life science community and society-at-large. He has developed effective strategies for a wide range of companies and organizations, from start-ups to some of the world’s largest life science companies. Chris is based in the Boston area and holds a PhD from UC San Diego. 

Guillaume Barbier, PhD – Guillaume Barbier is the VP of Research and Development at Provectus Algae. Gui has more than 15 years of experience as a leading research scientist in the biotech sector, with previous roles at Ginkgo Bioworks, Joyn Bio and Novozymes. Throughout his career, he has placed significant emphasis on biosustainability initiatives, including those augmenting and harnessing photosynthetic systems. He also holds extensive expertise in synthetic biology, protein engineering and purification, metabolic engineering, fermentation and high throughput project design. He also has more than six patents in the field of protein and metabolic engineering. Based in Noosa, Australia, Gui leads the development of Provectus Algae's microalgae library, biodiscovery platform, synthetic biology toolkit and bioprocess development efforts.

Nusqe Spanton – Nusqe Spanton is the founder and CEO of Provectus Algae. Nusqe is an aquaculture and algae expert with nearly two decades of experience working in international aquacultural production, marine biotechnology and corporate management. Nusqe is on a mission to make sustainable biomanufacturing a widespread commercial reality, using microalgae chassis to transform light and carbon dioxide into critical specialty ingredients. By applying modern automation, machine learning and synthetic biology approaches, Nusqe and Provectus Algae are unlocking microalgae’s full potential as a viable and scalable pathway for producing high-value chemicals and biologics. Provectus Algae’s end-to-end biomanufacturing platform, powered by its Precision Photosynthesis™ technology, has far-reaching applications in a variety of industries, including food & beverage, cosmetics, agriculture, therapeutics, and beyond.