Innovation trends in industrial biotechnology

2025-08-02    259

Industrial biotechnology: the glorious past, the challenging present, and a bright future
Industrial biotechnology mostly relies on manipulating and growing different types of bacteria, yeast, and filamentous fungi. Controlled microbial fermentations used by humans have been around since the dawn of civilization for the production of fermented foods and beverages [1]. During the early 20th century, the first industrial-scale fermentation processes were established for the production of chemicals, including acetone, butanol, and citric acid. Production of citric acid in 1919 by Aspergillus niger was a particular breakthrough as it was the first aerobic fermentation process and, hence, required the establishment of technologies that could ensure the provision of sterile air in large quantities to support the production process. This advancement paved the way for the aerobic industrial-scale production of penicillin during World War 2; shortly after the war, several novel processes were established for the production of a range of antibiotics. During the 1960s and 1970s, production of several different chemicals through microbial fermentation was established, such as for amino acids used in food and feed, and for industrial enzymes with a wide range of applications. With the introduction of genetic engineering during the early 1970s, the biotech industry was established for the production of proteins for pharmaceutical use [1]. This industry has grown substantially over the years and most top-selling drugs are now produced by fermentation (including cell cultures), with several being produced through microbial fermentation [2], including insulin and other hormones [3]. With the ability to engineer microorganisms, the idea of developing cell factories for production of an even wider range of products emerged. Several large-scale ventures were established, such as by the chemical company Eastman, which invested heavily in establishing the commercial production of dyes, including indigo. However, the technology for engineering microorganisms was not sufficiently mature, and most of these ventures did not deliver financially or at scale. With the genomics revolution of the early 2000s, based largely on shotgun genome sequencing and development of modern ‘omics analytics and data analyses of microorganisms, more data were obtained relating to microbial cells, which led to better understanding of their metabolic networks and physiology [4,5]. Based on these genomic data, it became possible to develop mathematical models describing the metabolism, first of the bacterium Escherichia coli [6] and then of the yeast Saccharomyces cerevisiae [7], two widely used cell factories and models for bacterial and eukaryal biology, respectively. It also became possible to further develop these genome-scale metabolic stoichiometric models (GEMs) beyond descriptive functions and to start using different additional data and constraints that yielded better predictions that could be confirmed experimentally [8]. In parallel, methods in genetic and genome engineering developed and gave rise to metabolic engineering (see Glossary) and later synthetic biology disciplines. All these conceptual, computational, and experimental approaches gave rise to cell factories currently used for the production of valuable chemicals, solvents, monomers, pharmaceuticals, nutraceuticals, antibiotics, and so on.
The challenges of industrial biotechnology have been partially due to limitations of scientific knowledge and available molecular and analytical tools, and partially due to social, political, and market forces. Conceptually, the challenge is still in the engineering itself: we do not yet know what ‘parts’ a cell has (all genes, all RNAs, all proteins, and all metabolites in conditions relevant for production) and how all the ‘parts’ work individually and interact together; in addition, we cannot predict how the ‘parts’ or the ‘whole’ will behave when the system is perturbed either genetically or environmentally (i.e., during the production process). Neither can we efficiently perform all potential modifications, and those that we can, such as by using CRISPR/Cas systems, cannot always be automated and scaled.
By contrast, the societal context in which these cell factories are supposed to perform has also been tumultuous. Much focus over the past 20 years has been on developing sustainable production processes for the replacement of petroleum-based or derived fuels, chemicals, and materials. Several large chemical companies, such as BASF, DSM, BP, and Total, established substantial projects and collaborations in the area of metabolic engineering. Furthermore, several start-up companies were established with the objective of developing novel bio-based production processes for sustainable chemicals. Efforts so far have often been on the production of commodity chemicals that could replace the key building blocks used in the chemical industry, as a result of the report published in 2004 and updated in 2010 by the US Department of Energy (DoE) [9]. This report provides a list of chemicals that could fit this need. Even though this has resulted in the establishment of a few large-scale processes for the production of sustainable chemicals (Box 1), the impact of these efforts has been relatively minor in transforming the petroleum-based chemical industry into a bio-based chemical industry. An example is the bioproduction of succinic acid: extensive academic research has been directed at engineering cell factories for succinic acid production by microbes [10] and several promising companies were established (Box 2). To the best of our knowledge, these research and commercial activities have been either terminated or production is at a very low level solely to support niche markets (Box 2). So far, industrial-scale production has only been established for two of the chemicals on the DoE list, namely lactic acid and itaconic acid, with lactic acid first added to the 2010 list after large-scale production had been established. Lactic acid is currently produced on a very large scale with an estimated market value exceeding US$2.5 billion, with most being used for the production of polylactate.

source origin：www.cell.com