Everything you need to know about molecular farming
Living organisms can be considered as biofactories, i.e., the producers of biologically active molecules, such as proteins and other macromolecules.
In simple terms, we can programme cells to become factories and express specific proteins as instructed (Catherin, T. 2022). This technology is based on the principles of recombinant protein production.
Biofactories also offer an undeniable solution for moving towards a sustainable economy in a world threatened by climate change, due to the depletion of finite natural resources, and environmentally unsustainable production practices.
Comparing biofactories
There are many different types of cells that can be used as protein factories, or expression systems; mammalian cells, insect cells, and plant cells, are all viable.
| Biofactory type | Expression system | Production method |
| Precision fermentation | Bacteria, yeast, mammalian cells | Microbes are grown in a large stainless-steel bioreactor where nutrients and heat are provided to enable fermentation, cell growth, and protein production. Once the fermentation process is complete, the target protein is recovered from the cells or fermentation broth |
| Molecular farming | Plant cells | The plant acts as a single-use bioreactor and are grown in fields, greenhouses, or vertical farms, with the desired proteins ultimately extracted from the plants |
What is molecular farming?
Molecular farming is the use of entire plants as expression hosts to produce recombinant proteins. DNA is inserted into the plant in a transient or stable manner and is then used as the code for the plant to synthesize the corresponding proteins, in this case growth factors and cytokines.
The protein of interest accumulates in the plant and must then be extracted and purified to obtain the final product.
Why does camelina sativa make an optimum biofactory?
We use an oilseed plant called Camelina sativa for the stable expression of recombinant proteins.
Camelina has many agronomic qualities and environmental attributes (e.g., adaptability to diverse environmental conditions, low requirements for water and nutrients and relatively strong resistance to insect pests and microbial diseases) (Christelle, L. et al 2022).
Among oilseeds containing interesting fatty acid profiles, Camelina is identified as one of the main candidates to be used in the future European bioeconomy. Moreover, Camelina´s oils are well known products in the cosmetic and food industries, being registered under the FDA ingredients list –GRAS-, making them ideal candidates as basal technologies to obtain innovative products.
Scaling-up a molecular farm
We have developed various technologies to increase the expression yield of these plants to make the extraction process more efficient and more scalable.
For example, we target our growth factors and other recombinant proteins to the seed compartment of the plant, which captures the benefits of the exponential scalability of agriculture where, once a stable plant line is obtained, each plant yields thousands of seeds that each give birth to a new plant, and so forth, without the need for any further transformation of the plant between the succeeding generations.
This enables a streamlined scale-up process where we employ agricultural practices and principles that have been in use for millennia by cultivating Camelina in open fields. To maximize the process, the cultivation can be done within areas with dozens of hectares, which enables to produce 10 kg of growth factors per hectare and per harvest (two harvests per year). This results in hundreds of kilograms of product per year.
Extraction and purification
Core Biogenesis’ bioproduction method leverages oleosin fusion technology, whereby plant oleosins are capable of anchoring onto the surface of natural or artificial oil bodies. The oleosin fusion expression systems allow products to be extracted with oil bodies.
In this case, the targeted isolation of the recombinant protein of interest to the lipid body, a specific organelle of the plant located in the seeds of Camelina sativa, allows for the development of phase-specific downstream processes that are scalable and guarantee a final product free from impurities.
How does the safety profile compare to traditional expression systems (e.g., post translational glycosylation?)
Camelina sativa offers several safety benefits over traditional production methods. One of the most important aspects relies on the lack of human and microbial pathogens, such as endotoxins, which reduces the risk of contamination and ensures the safety of the produced proteins. At the same time, the presence of unique post-translational modifications in plant-made proteins can simplify the purification process compared to proteins produced in other systems (Ilya, R. et al, 2002).
In this regard, plants can successfully perform the post- translational modifications required by most pharmaceutical proteins under development. Heterologous proteins requiring these modifications are usually retained in the endoplasmic reticulum (ER) using the C-terminal ER retention sequence KDEL or targeted into the protein secretion- modification pathway that delivers the recombinant proteins into the intercellular spaces (apoplast) via the ER and Golgi apparatus (Matilde, M. 2013). Both strategies also enhance protein expression significantly. Finally, unlike animal or insect cell cultures, plants do not support the replication of most viruses, reducing the risk of viral contamination.
Using plant-based expression systems to reduce COGs
Reducing COGs is essential for the future success of cell therapies, one of the ways to achieve this is through manufacturing efficiencies.
Plant biofactories can significantly reduce costs; culture, purification and scale-up are the key contributing factor to reducing COGs. Huge economies of scale savings can also be made through molecular farming without the need to create huge facilities to increase output.
Culture
Plants eliminate the high costs involved in the infrastructure and materials needed for the growth and expansion of these more traditional systems.
Purification
For the downstream purification, plant-specific methods provide a further reduction to the cost of goods (oleosin fusion).
Yield and scale-up
Scale-up in open fields make the process much more cost-efficient
Speak to us to discover how plant-based expression systems can impact your therapy development programs
References:
- Catherin, T. 2022. Plants as bioreactors: The next frontier for commercial-scale protein production? https://synthesis.capital/insights/plants-as-bioreactors
- Christelle, L. et al. 2022. Oil bodies from Chia (salvia hispanica L.), and Camelina (camelina sativa L.) seeds for innovative food applications: microstructure, composition, and physical stability.
- Ilya, R. et al. 2022. Plants and human health in the twenty first century. Trends in Biotechnology. Vol 20. No 12 (522-531).
- Matilde, M. et al. 2013. Comparative evaluation of recombinant protein production in different biofactories: the green perspective. Hindawi Biomedical Research International. Vol 2014 (1-14).
Core Biogenesis bags $10.5m funding to drive plant-based bioproduction
Core Biogenesis has completed a $10.5 million Series A funding round, which will be used to build a plant-based bioproduction facility.
The site will be located in Strasbourg, France and the firm said it will be dedicated to manufacturing growth factors and cytokines for the cell therapy space and cellular agricultural industry and will launch early next year.
The firm claims it has developed a technology platform that can express recombinant proteins from the seeds of a Camelina sativa oilseed plant.
“A robust oilseed crop, Camelina sativa, can be engineered to generate a stable seed line for a recombinant protein, such as a growth factor,” a spokesperson for the firm told us.
“They plant these crops on a farm and grow them as any other crop – to produce seeds. In their case, the seeds express recombinant proteins. When the plants produce seeds, the seeds are harvested from the farm and the recombinant protein is recovered from the seeds through a mechanical grinding, centrifugation, and simple purification process. This platform has incredible scalability. For example, a 1-hectare farm is the equivalent growth factor capacity of a 10,000 L traditional bioreactor.”
While the firm’s molecular farming platform can be used to express recombinant growth factors for therapeutics and cultivated meat, Core Biologics says that its focus is to respond to the intricate and high costs of next-generation therapeutic modalities, like cell therapies.
Additionally, the spokesperson said the advantages of using a plant-based production systems is that there are “lower cost process, no risk of viral or endotoxin contamination (since the process is animal-free), high levels of bioactivity in the resultant proteins, and the entire process is carbon negative.”
The funding will also be used to hire additional members of staff to support the expansion and Core Biogenesis said the location means while there is much competition in the space, “there is no shortage of scientists.”
Core Biogenesis reels in $10.5M in series A to build new plant cell facility
Core Biogenesis, a French biotech startup that specializes in plant-based cell therapy manufacturing, reeled in $10.5 million in series A funding to build a new production facility.
The company, which was founded in 2020, said it will construct a new facility to produce growth factors and cytokines for the expanding cell therapy market and cellular agriculture industry. The startup will also use the funds to hire scientific and technical staff at the plant, which is expected to operational by the first quarter of 2023.
Following the explosive growth of mRNA vaccines in the wake of the COVID-19 pandemic, drug developers have begun investing in plant-based technologies for future vaccines and treatments, Core Biogenesis says. For its part, Core's tech uses flax seed to produce proteins that are extracted and purified to create raw materials that can be used in pharmaceuticals.
"We achieve high yield while eliminating the biosafety risk of endotoxin, virus, and prion contamination seen with current mammalian and microbial expression platforms,” Alexandre Reeber, chief executive and a co-founder of Core Biogenesis, said in a statement.
Although the company’s molecular farming platform can capture recombinant growth factors ranging from human therapies to cultivated meats, Core Biogenesis says it's focused on driving down the high costs and complex nature of next-gen therapies such as cell therapies. The company estimates the cell therapy market will grow from $9.2 billion last year to $65 billion by 2027.
Ange, a Paris-based science and technology venture capital firm, led the round. Other investors included Blue Horizon Ventures and Thia Ventures.
Core won't be alone in exploring plant-based manufacturing applications in biopharma. More than a year ago, GSK partner Medicago said it was taking COVID-19 vaccine production into the greenhouse. Dubbed Covifenz, the vaccine won approval in Canada in February.