In this blog post, we’ll explore the principles of biological metabolism, the core technologies of metabolic engineering—which analyze and manipulate microbial metabolic pathways—and the current state and future of metabolic engineering as it expands into areas such as biofuels, chemicals, pharmaceuticals, and biodegradable materials.
What is metabolism, and why have microorganisms garnered so much attention?
Currently, the scientific community is actively developing various technologies to reduce dependence on fossil fuels or replace them. This includes research aimed at producing necessary materials from renewable resources, and efforts to apply biotechnology for this purpose are underway worldwide. Metabolic engineering has emerged as a key technological field within this trend. The World Economic Forum has identified synthetic biology and metabolic engineering as one of the key emerging technologies capable of influencing future social, economic, and environmental issues, and has since continued to highlight systems metabolic engineering as a technology for the sustainable production of chemicals and fuels. So, what exactly is metabolic engineering, which is receiving so much attention?
Before exploring what metabolic engineering is, let’s first understand metabolism. Metabolism refers to the process by which an organism breaks down or synthesizes nutrients taken in from outside the body to produce the components of living organisms or the substances and energy necessary for life, while excreting unnecessary substances from the body. Metabolism also occurs within our own bodies. The process of converting the food we eat into a form that can be absorbed is one of the essential metabolic processes in our bodies. Furthermore, the process of converting these absorbed nutrients into the energy needed to move our muscles and read this article is also part of metabolism. This metabolic activity occurs not only in humans but in all living organisms.
Engineers have sought to identify metabolic processes among the countless ones found in living organisms that produce useful substances and utilize them for production. Among these, microbial metabolism has begun to attract attention as a means of producing materials. Microorganisms offer the advantages of being relatively easy to engineer—both genetically and physiologically—and to culture, and they can be applied to various fields such as chemistry, pharmaceuticals, agriculture, and energy. Furthermore, biological production using microorganisms is being researched as a sustainable manufacturing method because it can produce various substances through pathways different from those of chemical synthesis. However, in some cases, it is difficult to achieve industrial-scale productivity relying solely on the natural production capacity of microorganisms, and unwanted byproducts are sometimes produced alongside the desired substances. Therefore, complex separation and purification processes may be necessary to obtain the required substances with high yields and productivity. Metabolic engineering is a technology developed to address these challenges. Metabolic engineering refers to a series of techniques that design and modify the metabolic characteristics of microorganisms to enable them to produce more of the desired substances and reduce the production of unwanted substances.
What technologies does metabolic engineering encompass?
So, specifically, what technologies does metabolic engineering include? First, it includes technologies for analyzing microbial metabolic flux. Countless metabolic reactions occur within a single organism, and the chemical reactions involved are also extremely numerous. Even in a relatively simple microorganism like E. coli, numerous metabolic reactions are interconnected, and since each metabolic pathway can influence the others, the individual reactions do not operate completely independently. To understand such a complex system, it is essential to analyze the metabolism of the entire microorganism or specific parts of it and determine how each metabolic reaction and pathway is connected. Recently, by combining genomic data with metabolomics, metabolic flux analysis, and computer modeling, scientists have been able to understand with greater precision how substances move and are consumed within cells. Therefore, before modifying a microorganism’s production capacity, it is necessary to develop technologies to identify and characterize what is happening inside the microorganism; this analytical process is also a crucial part of metabolic engineering.
The second is the technology for manipulating the major metabolic pathways of microorganisms. The process of modifying microorganisms based on the analysis of their metabolic systems is a core technology for practical application in production processes. This technology uses techniques such as genetic recombination and gene editing to remove or amplify existing metabolic pathways in microorganisms and, when necessary, introduce or modify new pathways, thereby enabling microorganisms to produce more of the target metabolite and reduce the generation of byproducts. Furthermore, it is possible to introduce new metabolic pathways into microorganisms that do not naturally exist in them. In fact, there is a case where specific biosynthetic genes were introduced into E. coli to enable it to produce PHA, a biodegradable plastic material that it previously could not produce. Thus, the technology for modifying microbial metabolic pathways to suit specific purposes is a core area of metabolic engineering.
Finally, there is the technology for developing microorganisms optimized for production processes. Simply obtaining a microorganism with the desired metabolic pathway does not mean it can be immediately applied to a production process. Even microorganisms that exhibit high productivity in the laboratory may experience reduced productivity or fail to survive stably if they cannot adapt to the environmental conditions used in actual production processes—such as culture conditions, raw materials, temperature, pH, and oxygen supply. Therefore, technologies for further improving engineered microorganisms to suit actual production environments, or for establishing efficient cultivation and process conditions that allow microorganisms to maintain high productivity, are also crucial components of metabolic engineering. Today, research is underway to reduce trial and error and accelerate development by integrating computer modeling, automated experiments, and artificial intelligence into these strain development and process optimization efforts. The U.S. Department of Energy is also conducting research to accelerate the commercialization of bio-based fuels, chemicals, and materials by utilizing technologies that combine microbial optimization, automated experiments, and artificial intelligence in the fields of metabolic engineering and biomanufacturing.
How is metabolic engineering evolving into a sustainable production technology?
Processes utilizing metabolic engineering—which is gaining attention as a sustainable and eco-friendly production method—can offer several advantages compared to traditional chemical processes. Unlike some chemical processes that require maintaining conditions such as high temperature and high pressure for efficient chemical reactions, metabolic engineering processes using microorganisms can proceed under relatively mild conditions. Furthermore, metabolic engineering allows for the manipulation of microbial metabolic pathways to increase the yield and productivity of target products while reducing the generation of impurities or byproducts, thereby potentially lowering the costs associated with separation and purification. Furthermore, cost reductions can be expected through shorter process times, as well as savings in equipment and raw material costs. However, these advantages do not automatically apply to all products and processes; to secure true industrial competitiveness, factors such as raw material prices, strain performance, fermentation scale, separation and purification costs, and process stability must be comprehensively considered.
Because they utilize microorganisms, metabolic engineering processes have the potential to broaden the range of substances that can be produced. In particular, substances that are difficult to produce through chemical synthesis or direct extraction from natural sources can be manufactured by designing microbial metabolic pathways. For example, research is underway to use microorganisms to produce proteins for specialized materials—such as spider silk protein—as well as recombinant proteins for specific purposes and various pharmaceutical and chemical raw materials. Metabolic engineering is also being utilized in the production of biofuels, bio-based chemicals, and biomaterials. Recently, there has been active research aimed at reducing dependence on fossil resources by combining fermentation using renewable carbon sources with biomanufacturing technologies. As such, metabolic engineering holds significant industrial potential in terms of production costs and the diversity of production methods.
In the past, industrial applications of metabolic engineering were primarily limited to the production of enzymes, antibiotics, amino acids, and bio-based chemicals. As technology has advanced, the scope of metabolic engineering has expanded to include biofuels, biodegradable materials, specialty chemicals, pharmaceutical raw materials, and protein-based materials. Systems metabolic engineering has become increasingly sophisticated through integration with technologies such as synthetic biology, systems biology, evolutionary engineering, and metabolic flux analysis, and research continues to expand the variety and productivity of substances produced by microorganisms. The World Economic Forum also explains that systems metabolic engineering has evolved into a sustainable technology for producing fuels, pharmaceuticals, and chemicals using microorganisms.
Currently, the scope of research in the field of metabolic engineering is expanding into various areas, including substance production using plant tissues—in addition to microorganisms—and research on human metabolic disorders. Furthermore, to enhance the industrial application of biomanufacturing technologies, research is underway to integrate not only the design and optimization of metabolic pathways but also cultivation processes, bioreactors, separation and purification, and process scale-up into a single production system. The U.S. Department of Energy supports research that integrates metabolic pathway engineering and optimization, the scaling up of biomanufacturing, automation, and digital technologies to produce bio-based fuels, chemicals, and materials. Concurrently, it is also researching biological processes that utilize carbon dioxide as a carbon source to convert it into useful substances.
In the future, metabolic engineering is expected to play an increasingly important role not only in biotechnology, bioenergy, and healthcare but also in various sectors such as the pharmaceutical, chemical, environmental, and materials industries. In particular, as genome sequencing, gene editing, metabolic flux analysis, artificial intelligence, and automated experimental techniques converge, technologies are advancing that enable the design of microorganisms with desired functions and their rapid integration into actual production processes. These developments have the potential to contribute to the transition of certain sectors of traditional industries—which have relied on fossil resources for material production—to bio-based production methods. Globally, research is expanding to produce fuels, chemicals, and materials through biomanufacturing and to utilize renewable resources or new carbon sources such as carbon dioxide. Metabolic engineering is evolving beyond simply modifying microorganisms into a technology that understands and designs biological metabolic systems to efficiently produce necessary materials, and it is expected to have a significant impact on the future of biotechnology and the biomanufacturing industry.
