Author: Martin Trinker
In the dynamic world of biotechnology, mammalian cell cultures and microbial fermenters have long dominated as the primary tools for bioproduction. However, an unconventional contender is quietly emerging: plant-cell-based production systems. Once overshadowed by established methods, plant-cell bioreactors are now demonstrating their potential to produce pharmaceuticals and other high-value compounds efficiently and sustainably. This is the inspiring story of molecular farming—a journey of innovation, resilience, and groundbreaking progress.
The Genesis of Plant-Cell Bioreactors
The story begins with Agrobacterium tumefaciens, a soil bacterium notorious for causing crown gall disease in plants. In the late 1970s, researchers discovered that this bacterium could transfer a segment of its DNA, known as T-DNA, into the genome of host plants, leading to tumor formation. This natural gene transfer mechanism intrigued scientists, prompting them to explore its potential for genetic engineering.
By the early 1980s, pioneering work by Marc Van Montagu and Jeff Schell had elucidated the gene transfer mechanism of Agrobacterium, laying the groundwork for plant genetic engineering. They demonstrated that the T-DNA could be modified to carry foreign genes, effectively turning plants into biofactories for recombinant proteins. This breakthrough marked the inception of plant molecular farming, where plants are engineered to produce specific proteins for pharmaceutical and industrial applications.
Early Milestones: From Concept to Application
The first significant achievement in plant molecular farming was the expression of human serum albumin in transgenic tobacco and potato plants in 1990. This accomplishment showcased the feasibility of producing complex human proteins in plants, sparking interest in the field.
Concurrently, the development of plant cell suspension cultures offered a controlled environment for producing valuable compounds. Unlike whole plants, these cultures allowed for precise control over growth conditions, leading to consistent and scalable production.
The Bioreactor Breakthrough: Precision Meets Nature
Imagine a clean, stainless-steel tank filled not with microbial or animal cells but with plant cells suspended in a nutrient-rich liquid. These tiny, undifferentiated cells, often derived from species like tobacco (Nicotiana tabacum) or carrot (Daucus carota), divide and produce biomolecules just as they would in a natural environment—only now, under human direction.
One of the first significant breakthroughs in plant-cell bioreactor history involves the production of shikonin, a bright red pigment with anti-inflammatory and anti-tumor properties, derived from the roots of Lithospermum erythrorhizon. Traditionally harvested from plants in the wild, shikonin production faced challenges due to overharvesting and slow plant growth. In the 1990s, Japanese researchers developed a plant-cell culture system that produced shikonin in bioreactors, allowing for industrial-scale production.
Safety: Intrinsic Resistance to Mammalian Pathogens
One of the most compelling advantages of plant-cell-based production systems is their intrinsic resistance to mammalian pathogens. Unlike mammalian cell cultures, plant cells are not susceptible to contamination by viruses and prions that affect humans. This inherent safety reduces the risk of pathogen transmission in biopharmaceuticals, ensuring compliance with stringent safety standards and potentially lowering the costs associated with purification and validation processes.
Unique Capabilities: Producing the Impossible
One of the most remarkable advantages of plant-cell-based systems lies in their ability to produce complex and specialized proteins that are challenging, if not impossible, to manufacture using conventional production systems, including toxins. Plant cells leverage their eukaryotic machinery to ensure proper protein folding and post-translational modifications, crucial for the biological activity of toxins. Unlike microbial or mammalian systems, plant cells can produce these proteins without being adversely affected by their toxic nature, thanks to their unique cellular pathways and compartmentalization. This makes plant-cell-based systems an ideal platform for producing toxins for research, therapeutic applications, and industrial uses.
Cost-Effectiveness: The Economic Advantage of Molecular Farming
Mammalian and microbial cell cultures require carefully formulated growth media, often enriched with serum, amino acids, vitamins, and other expensive additives. In contrast, plant cells thrive on simpler, low-cost media composed of basic nutrients like salts, sugar, and minimal trace elements. These requirements significantly reduce the ongoing expenses associated with large-scale production.
For instance, producing monoclonal antibodies in mammalian cells often requires serum derived from fetal bovine blood, a costly and ethically sensitive input, or expensive recombinant growth factors. In molecular farming, plant cells synthesize the same proteins without the need for such premium components, slashing costs while aligning with sustainability goals.
A New Era of Bioproduction
Plant cell-based molecular farming in bioreactors is no longer just a novel concept—it’s a proven, scalable solution reshaping biotechnology. From Protalix’s FDA-approved Elelyso™, a treatment for Gaucher’s disease, produced in carrot cells, to Greenovation Biotech’s moss-derived complement factor H, a protein involved in immune regulation and VTT’s eco-friendly cellular coffee, these success stories showcase the versatility and impact of this technology. By combining cost-effectiveness, sustainability, and intrinsic safety from mammalian pathogens, plant cell cultures are driving innovation across pharmaceuticals, agriculture, and even consumer goods. As researchers like Johannes Buyel continue to push the boundaries with plant-based production in bioreactors, the future of molecular farming promises a revolution in bioproduction, where efficiency and environmental stewardship go hand in hand. The era of plant cells as biofactories has arrived—and it’s transforming industries at their very roots.
Remaining Challenges Plant Cell-Based Molecular Farming
Despite its promise, molecular farming still faces some significant hurdles:
- Scaling Production: Plant cells are sensitive to mechanical stress in bioreactors, posing challenges for large-scale production. Advances in wave and airlift bioreactors are helping to mitigate these issues.
- Metabolic Optimization: Engineering plant cells to efficiently produce target biomolecules requires advanced tools like CRISPR-Cas9 and synthetic biology.
- Regulatory Complexity: Navigating the stringent approval processes for biopharmaceuticals remains a barrier to widespread adoption.
- Economic Feasibility: While plant-cell systems reduce operating costs, initial setup and optimization expenses can be high, requiring careful investment and long-term planning.
Addressing these challenges is essential to unlocking the full potential of molecular farming.
Fortunately, ongoing research and innovation, also at the Austrian Centre of Industrial Biotechnology (acib) are delivering solutions, solidifying this platform as a sustainable and versatile alternative to traditional production methods.
Conclusion
The ascent of plant-cell-based production systems from obscurity to prominence exemplifies the classic underdog narrative. Through innovation, perseverance, and strategic leveraging of their unique advantages—such as safety from mammalian pathogens—plant cells have carved out a significant niche in the biotechnology landscape. As research progresses and more success stories emerge, plant-cell bioreactors are poised to play an increasingly vital role in the sustainable and efficient production of biopharmaceuticals and beyond.
Picture by acib