Molecular farming – The slope of enlightenment

Abstract

Molecular farming can be defined as the use of plants to produce recombinant protein products. The technology is now >30 years old. The early promise of molecular farming was based on three perceived advantages: the low costs of growing plants, the immense scalability of agricultural production, and the inherent safety of plants as hosts for the production of pharmaceuticals. This resulted in a glut of research publications in which diverse proteins were expressed in equally diverse plant-based systems, and numerous companies were founded hoping to commercialize the new technology. There was a moderate degree of success for companies producing non-pharmaceutical proteins, but in the pharmaceutical sector the anticipation raised by promising early research was soon met by the cold hard reality of industrial pragmatism. Plants did not have a track record of success in pharmaceutical protein manufacturing, lacked a regulatory framework, and did not perform as well as established industry platforms. Negative attitudes towards genetically modified plants added to the mix. By the early 2000s, major industry players started to lose interest and pharmaceutical molecular farming fell from a peak of expectation into a trough of disillusionment, just as predicted by the Gartner hype cycle. But many of the pioneers of molecular farming have refocused their activities and have worked to address the limitations that hampered the first generation of technologies. The field has now consolidated around a smaller number of better-characterized platforms and has started to develop standardized methods and best practices, mirroring the evolution of more mature industry sectors. Likewise, attention has turned from proof-of-principle studies to realistic techno-economic modeling to capture significant niche markets, replicating the success of the industrial molecular farming sector. Here we argue that these recent developments signify that pharmaceutical molecular farming is now climbing the slope of enlightenment and will soon emerge as a mature technology.

Introduction

Molecular farming can be defined as the production of recombinant proteins¹ in plants, where the aim is to recover and utilize the protein product rather than the plant itself (Ma et al., 2003; Stoger et al., 2014; Tschofen et al., 2016). The target protein is either extracted and purified or used as part of a crude extract, whereas the plant is merely a host and is either discarded and destroyed at the end of the process or utilized as a separate side-stream (Buyel, 2019). Molecular farming often involves the use of whole terrestrial plants such as tobacco and cereals, but the technology also encompasses other plant-based systems, including plant cell and tissue cultures (Santos et al., 2016), aquatic plants (Everett et al., 2012), moss (Decker and Reski, 2012), algae (Rosales-Mendoza et al., 2012), and even in vitro transcription and translation systems derived from plant cells (Buntru et al., 2014). The diversity of these plant-based systems means that molecular farming comprises a range of different platforms that have the potential to compete in many different markets, ranging from technical enzymes and research reagents that are typically produced in bacteria and yeast, to biopharmaceutical proteins that are usually produced in mammalian cells, particularly Chinese hamster ovary (CHO) cell lines (Schillberg et al., 2019).

The ability to compete across different markets reflects the specific advantages of the individual plant-based systems. For example, transgenic plants are inexpensive and massively scalable compared to CHO cells (Buyel et al., 2017), transient expression systems allow production to be scaled up much more quickly than any fermenter-based platform (Hiatt et al., 2015; Holtz et al., 2015), and plant cells offer the ability to produce uniquely tailored glycan structures (Schillberg et al., 2017; Fischer et al., 2018). All plant-based systems can be considered intrinsically safer than mammalian cells for pharmaceutical products because they do not support the replication of mammalian viruses (Hundleby et al., 2018). They also address consumer demands for products that are ‘certified animal free’ (Spiegel et al., 2018). Despite these advantages, molecular farming in plants has not supplanted the current generation of industrial recombinant protein manufacturing technologies and only a handful of products have reached the market (Fischer et al., 2014; Schillberg et al., 2019). In this review article, we consider the reasons for this slow progress, evaluate the latest generation of molecular farming platforms from an economic perspective, and predict how the technology may evolve in the future.