【Frontiers of HaiChuan Chemical Technology】Opportunities and Challenges in Synthetic Biology for the Production of Bulk Chemicals

1 Current Status of Bulk Chemical Production Bulk chemicals are those that are produced using basic chemical raw materials; they are manufactured and consumed in large quantities, have relatively low prices and added value (with prices below $2 per kilogram), but they play an important supporting role in the downstream industrial chain； Bulk chemicals also serve as raw materials or intermediates for many other chemical products, with a wide range of applications. It is commonly used in industries such as plastics, rubber, textiles, coatings, pharmaceuticals, and food, with an annual production volume of 100,000 tons or even over 1 million tons. These chemicals not only affect the development of numerous industries downstream, but are also directly related to the **stable operation of the socio-economy. Bulk chemicals mainly include “triphenyls,” “trienes” and their downstream product chains, as well as energy chemicals. Currently, the global annual production of bulk chemicals exceeds 3 billion tons, with a market size reaching trillions of dollars. “\"Triphenyls\" include benzene, toluene, and xylene; the downstream industries derived from them encompass products such as styrene, caprolactam, phenoxymethane, p-xylene, benzoic acid, benzonitrile, benzyl acetate, terephthalic acid, and adipic acid. In 2023, the global total production of benzene alone reached 78.8 million tons. “\"Trienes\" refer to ethylene, propylene, and butadiene; their downstream products include polyethylene, styrene, polypropylene, acrylonitrile, acetone, synthetic rubber, and resins, among other materials. Taking ethylene as an example, one of the organic chemical raw materials with the highest global production volume, its global production in 2023 approached 200 million tons, with a market value of over 180 billion dollars. These massive amounts of data not only highlight the importance of bulk chemicals but also reflect the global reliance on chemical products. However, along with its massive production volume and market scale, the traditional petrochemical industry also imposes significant environmental costs. According to statistics, the global chemical industry emits over 2 billion tons of carbon dioxide each year, accounting for about 7% of total industrial carbon emissions worldwide. For example, the steam cracking process used in ethylene production takes place at high temperatures of over 800°C, resulting in high energy consumption; approximately 1.5 tons of carbon dioxide are emitted for every ton of ethylene produced. It is estimated that by 2030, greenhouse gas emissions from the petrochemical industry will reach 2.8 billion metric tons of carbon dioxide equivalent (Mt CO2e). Currently, the level of CO2 in the atmosphere has risen from 280 ppm before industrialization to around 420 ppm, posing significant challenges to sustainable social development. Therefore, how to reduce carbon emissions and environmental impact while ensuring a continuous supply of bulk chemicals has become an important issue that the global chemical industry urgently needs to address. Biomanufacturing, as a green production method based on renewable resources, offers a new approach to solving this problem. Through microbial fermentation and metabolic engineering, low-carbon and sustainable production of chemicals can be achieved, which holds the potential to drive a green transformation in the chemical industry. However, biomanufacturing still faces many challenges in terms of cost, efficiency, and scale-up.

2 Current status of the production of bulk chemicals via traditional fermentation methods At present, various bulk chemicals derived from natural products can be produced biologically, such as organic acids, amino acids, polyols, and polyol sugars. The strong competitiveness of these biomanufacturing processes based on traditional fermentation methods is primarily attributed to the efficiency of the organisms’ own synthesis systems; this efficiency also enables biomanufacturing to produce large quantities of chemicals on a large scale, thus serving as the foundation for new forms of productivity. The cost of biomanufacturing mainly depends on output, yield, and production efficiency. These indicators are closely related to factors such as the catalytic efficiency of enzymes, the length of the pathway, and the regulatory efficiency of the metabolic network. Current status of biomanufacturing of products via short-path biosynthesis. Products synthesized through short-path biosynthesis are compounds that are produced directly from monosaccharides as starting materials, through the transformation of intermediates in central metabolic pathways such as glycolysis and the tricarboxylic acid cycle. Such products mainly include organic acids and sugar alcohols, with typical examples being gluconic acid, lactic acid, and ethanol. Ethanol can be used to produce beverages, flavors, and fuels, among other things, and it has a wide range of applications in industries such as chemicals, food, medicine, and agriculture. Ethanol is a natural product of microorganisms such as yeast. Its synthesis pathway is relatively short: glucose is converted to pyruvate through glycolysis, and then pyruvate is decarboxylated and reduced to ethanol – a process that involves 11 steps in total. The enzymes that catalyze these reactions are highly efficient; as a result, ethanol can now be produced using biological methods instead of petrochemical processes. At present, the first-generation bioethanol technology is already quite advanced; the ethanol concentration can reach around 17%–20% (by volume). Water and energy consumption are gradually decreasing, and zero wastewater discharge is achieved through water recycling techniques, enabling clean production throughout the entire process. In 2023, global bioethanol production reached 100 million tons, with the United States remaining the world’s largest producer of bioethanol, accounting for over half of the global market share ； Brazil is the second-largest producer, accounting for about 1/3 of the market share ； China’s bioethanol production is around 3.4 million tons, with the market price of the product at approximately 7,000 yuan per ton. In addition to using glucose to produce ethanol, in order to further reduce costs and improve efficiency, optimizing or replacing substrates for ethanol production has become a focus of research. One approach that has been well studied is the use of cellulose for ethanol production; this not only reduces production costs but also helps address carbon emission issues, contributing to the achievement of the \"dual carbon\" goals (Table 1). At present, cellulose ethanol production in our country adopts an alcohol-electricity-gas co-production model, achieving a carbon emission reduction rate of 90% over the entire life cycle. Another approach to cellulose ethanol is to use whole corn plants as raw material. Recently, several ethanol plants in the United States have begun using this technology, resulting in an increase in ethanol production of about 10%. Furthermore, ethanol can be produced using waste gases such as coal-derived syngas and emissions from steel production, which holds promise for further reducing the cost of bioethanol.

Current status of production of products via long-pathway biosynthesis. Products synthesized through long-pathway biosynthesis are those that are produced from monosaccharides as starting materials, with intermediate metabolites generated via central metabolic pathways and further transformed through multiple reaction steps. Such compounds mainly include amino acids and their derivatives, such as lysine and tryptophan. Lysine is an essential amino acid for the human body, with functions such as promoting growth and enhancing immunity. Common foods contain low levels of lysine, and it is easily lost during food processing; therefore, additional supplementation is necessary, and it is often used as an important dietary supplement. At the same time, lysine is also commonly used in areas such as animal feed, pharmaceuticals, and cosmetics. Since microorganisms can naturally produce lysine, it is currently produced mainly through microbial or enzymatic methods; the microbial method involves using Corynebacterium glutamicum or Escherichia coli. During the biosynthesis in Escherichia coli, lysine is produced from aspartate via 4 enzyme-catalyzed steps to form aspartate semialdehyde, and then through 6 further reactions to form diaminopimelic acid; this compound is subsequently converted into lysine by a decarboxylase enzyme. Starting from aspartate, the reaction involves 11 steps; if calculated based on the carbon source glucose (via glycolysis and the citric acid cycle to produce aspartate), it amounts to 30 steps. Even after such a lengthy reaction time, the highest yield reported to date is 240 grams per liter, with a yield rate of up to 68%, which demonstrates the efficiency of biological reactions and confirms the great potential of biomanufacturing (Table 1). This progress has also led to a significant reduction in the production cost of lysine, from 140,000 yuan per ton initially to 8,000 yuan per ton, bringing the cost level in line with that of chemical methods. Our country is a major producer of lysine, with Ningxia Yipin Bio-Technology Co., Ltd., Meihua Group, and Fufeng Group being the key manufacturers. Meihua Group is capable of producing millions of tons of lysine per year, giving it the highest production capacity in the world. In 2021, the global lysine market size reached 3.55 million tons, with China accounting for 73.3% of the world’s lysine supply. However, as global lysine production capacity becomes saturated, lysine prices continue to decline, posing new challenges to the yield and efficiency of lysine biosynthesis. Similarly, long-pathway products such as threonine, tryptophan, and erythritol are also substances that microorganisms can produce on their own; the efficiency of these pathways and the catalytic activity of the enzymes involved are relatively high. However, due to the longer production pathways for these products and the fact that they mainly arise from branched metabolic pathways, the yield from the original pathways is low. Through years of refinement using traditional fermentation methods such as strain selection, mutagenesis, and optimization of fermentation processes, the production of these products has seen improved yields and output, ultimately reducing their costs to be equal to or lower than those of chemical methods, thereby enabling industrial-scale production.

3 Current Status of the Biosynthesis of Bulk Chemicals Using Synthetic Biology Techniques: With the development of synthetic biology, the traditional biomanufacturing industry has undergone transformative changes. This technology endows microorganisms with powerful synthetic capabilities, significantly increasing the yield, productivity, and efficiency of target products. In recent years, researchers have employed synthetic biology approaches such as designing or modifying biosynthetic pathways, identifying or optimizing key enzymes, and performing gene editing on host cells to precisely design and optimize microbial cell factories. Breakthroughs have been achieved in the biosynthesis of certain bulk chemicals, providing new methods for their production. Current status and challenges in the biosynthesis of 1,3-propanediol. 1,3-Propanediol is widely used in the synthesis of drugs, polypropylene terephthalate (PTT), pharmaceutical intermediates, and antioxidants, and is applied in fields such as pharmaceuticals, cosmetics, and material manufacturing. Currently, over 90% of the industrial production of 1,3-propanediol worldwide is carried out using bioproduction methods. DuPont in the United States was the first to initiate research on producing 1,3-propanediol using biological methods. Initially, glycerin was used as the starting material, but due to its high cost and the difficulty in controlling its reducing power, DuPont switched to using glucose as the starting material. By integrating the glycerol synthesis pathway of Saccharomyces cerevisiae and the 1,3-propanediol synthesis pathway of Klebsiella pneumoniae into Escherichia coli, and optimizing the glucose transport system, this method increased the yield of 1,3-propanediol to 135 grams per liter, with a conversion rate of 83% (on a molar basis) (Table 1). Based on this technology, DuPont has maintained a global monopoly on the production of 1,3-propanediol. In 2019, DuPont in the United States completed its second expansion, bringing its production capacity to 80,000 tons per year. According to statistics from Beijing Hengzhou Bozhi International Information Consulting Co., Ltd., the global sales volume of 1,3-propanediol in 2023 was 222 million dollars, and it is expected to reach 469 million dollars by 2030. In 2020, China’s demand for 1,3-propanediol was around 60,000 tons, with imports accounting for 33,500 tons, representing a share of 55.8%. In contrast, in 2014 and 2018, the import share was 100% and 88.8% respectively, indicating a severe shortage in production capacity. Therefore, in order to break through the technological blockade imposed by the American company DuPont, domestic research institutions have also begun conducting research on the biological production of 1,3-propanediol. Institutions such as Tsinghua University and East China University of Science and Technology have achieved industrial application of the technology to produce 1,3-propanediol using glycerol as a carbon source. However, due to the high cost of glycerol, domestic processes still lack price competitiveness; moreover, the bio-refining technology needs improvement, which results in low conversion rates and excessive production of the by-product 2,3-butanediol, thereby increasing production costs. In 2022, Tsinghua University developed a new production process for 1,3-propanediol using monosaccharides such as glucose on a scale of tens of thousands of tons, breaking the technical monopoly held by the American company DuPont. It is believed that with the continued advancement of synthetic biology technology, further breakthroughs will be achieved in the biological production of 1,3-propanediol in China. Current status and challenges in the biosynthesis of 1,4-butanediol. As an important chemical raw material, 1,4-butanediol is primarily used in the production of polybutylene terephthalate (PBT). It also serves as an excellent solvent and humectant, and can be utilized in the manufacture of plasticizers and drugs, among other applications, thus having a wide range of uses. In 2011, the American company Genomatica published an article in Nature Chemical Biology in which it developed a biosynthetic pathway for 1,4-butanediol through route prediction and assembly, achieving a yield of 18 g/L. Subsequent further optimization of the enzyme activities in the metabolic pathway increased the yield of 1,4-butanediol to 200 g/L, with a yield of approximately 0.4–0.45 g/g (Table 1). Leveraging this technical advantage, the company has currently licensed multiple companies in the United States, Italy, Japan, Germany, and other countries to produce 1,4-butanediol. In 2013, the company collaborated with the American company DuPont to produce over 2,000 tons of 1,4-butanediol. In the same year, the company jointly built a 1,4-butanediol production line with German company BASF, with an annual capacity of 30,000 tons. In 2016, the company collaborated with the Italian company Novamont to establish a production line for manufacturing 1,4-butanediol via biological methods, which is used in the production of bioplastics; this marked the entry of its production of bio-based 1,4-butanediol into an industrializable phase. In 2021, the company further formed a joint venture with the U.S.-based Cargill and the German Helm Group to build a production line in the United States capable of producing 65,000 tons per year of 1,4-butanediol. Through this series of R&D and commercialization efforts, the American company Genomatica has gradually become the leading provider of technology and a key player in the global market for bio-based 1,4-butanediol. However, despite the significant environmental advantages of producing 1,4-butanediol through biological methods, which align with the goals of sustainable development and are supported by policies and subsidies, its price remains higher than that of traditional chemical synthesis methods. Currently, the production cost of bio-based 1,4-butanediol is approximately 9,000 yuan per ton, which is still higher than the 7,000 yuan per ton cost of the chemical synthesis method. Therefore, although the market demand for bio-based 1,4-butanediol is gradually increasing, especially in the production of biodegradable bio-based plastics and polyesters, its market share remains small. In 2024, the market size of bio-based 1,4-butanediol is expected to be around 39,000 tons. Analysis of the market size and share of bio-based 1,4-butanediol. It is worth noting that as global environmental regulations become increasingly stringent and the complexity and costs of chemical processes rise, 1,4-butanediol produced by biological methods is gaining more opportunities in the market. In recent years, the market supply of 1,4-butanediol has gradually become strained and its prices have continued to rise, which has created more market opportunities for biomanufacturing. Nevertheless, bio-manufacturing 1,4-butanediol still faces significant challenges in cost control. As production processes are further optimized and large-scale manufacturing is advanced, its costs are likely to decrease over time, providing strong support for it to secure a place in the market.

4 Challenges and Key Factors in the Biological Production of Bulk Chemicals: The disciplinary foundations of biological manufacturing and the challenges it faces. The biosynthesis of bulk chemicals encounters numerous challenges, among which the most significant obstacle is the efficiency and low cost of existing petroleum-based chemical synthesis techniques. This is thanks to the synthetic chemistry techniques based on the chemical discipline, which have reached a very high level of maturity after hundreds of years of development. From 1828, when the German chemist Wöhler first synthesized urea using inorganic substances, to 1869, when Mendeleev published the periodic table of elements revealing the inherent relationships between chemical elements, the field of chemistry gradually developed a systematic theoretical framework that uncovered these relationships, laying a solid foundation for the progress of synthetic chemistry. Since then, through more than 200 years of effort, chemists have developed countless important chemical reactions and compounds. According to data published by Chemical Abstracts in the United States in 2025, with 150 million chemical reactions, the number of compounds has exceeded 279 million, reflecting the infinite potential of synthetic chemistry in creating new substances and producing new products. In contrast, synthetic biology, which is based on life sciences, started later. It was not until 1953, when Watson and Crick revealed the structure of DNA, that humanity began to understand life. Subsequently, through a series of studies such as decoding codons and the Human Genome Project, scientists moved on to the stage of selectively modifying life ； After nearly 70 years of development, and with the continuous advancement and maturation of technologies such as polymerase chain reaction (PCR), gene synthesis technology, and gene editing technology, humanity has just entered the stage of creating life. According to the official data from the enzymology database BRENDA, this database currently contains 6,674 enzymes ； The metabolic reaction database MetaCyc currently contains 19,020 biochemical reactions and 19,372 metabolites. Although these data are increasing year by year, compared to the vast databases of molecules and reactions in the field of chemistry, biosynthesis still lags far behind in terms of cumulative volume. At the same time, due to an insufficient understanding of the operating principles of biological systems, the potential of cell factories has not yet been fully exploited, and this gap directly affects the economic viability of biomanufacturing. The biological production cost of many bulk chemicals remains higher than that of petrochemical synthesis methods, resulting in a lack of market competitiveness. However, synthetic biology also offers unique advantages: it uses renewable resources as raw materials, making it environmentally friendly and sustainable. With continuous advancements in underlying technologies and deeper research, the potential for biosynthesis will be gradually unlocked. By addressing the key issues in the production of bulk chemicals step by step, it will become possible to achieve low-cost, green production of more such chemicals. Key factors in the biomanufacture of bulk chemicals In the biomanufacture of bulk chemicals, yield, productivity, and production rate are the three core indicators that determine production costs. These indicators directly affect the economic viability and competitiveness of biomanufacturing technology, while the potential of microorganisms to produce chemicals through their metabolic capabilities opens up broad application prospects for biomanufacturing. However, the number of bulk chemicals that have been industrialized to date remains limited, as their biosynthetic potential has not yet been fully exploited. Current technologies struggle to meet the requirements of high yield, high efficiency, and rapid production simultaneously, which keeps the cost of bio-based products higher than that of traditional petroleum-based products, thereby limiting their market competitiveness. To achieve the economic viability of bulk chemicals, the development of efficient cell factories is at the core of biomanufacturing. Cells that undergo natural evolution exhibit economy in growth and metabolism, with material and energy flows being allocated first to the pathways required for cell growth. In the synthesis of bulk chemicals, the dispersion of material and energy flows results in low conversion rates, making it difficult to overcome natural limitations. Artificially directing metabolic fluxes into production pathways enables cell factories to produce chemicals efficiently, but this requires a range of complex systems engineering efforts to optimize and modify various key areas.

For example: 1. It is necessary to design and obtain efficient and specific enzymes in order to increase the rate and efficiency of key reactions, thereby directing more of the material flow toward the desired pathway； 2. Based on these enzymes, an efficient and suitable exogenous pathway is constructed to enhance the product synthesis efficiency by improving the metabolic flow balance between the exogenous pathway and the endogenous metabolic network ； 3. Designing shorter biosynthetic pathways or more efficient new production routes can improve the efficiency of material and energy flow, thereby enhancing the economic viability of bulk chemicals ； 4. By means of system design, a metabolic network with high efficiency is constructed, and flexible yet robust regulatory mechanisms are established between pathways and host cells, enabling metabolic pathways to operate efficiently in dynamic environments. The allocation of material and energy flows in growth metabolism is reduced, and these flows are directed toward the production of target products in order to maximize the yield of the desired chemicals ； 5. Optimize the growth and metabolism of chassis cells, reduce their own consumption of energy and nutrients, and improve the utilization efficiency of carbon sources, thereby increasing the yield. Through these designs, modifications, and optimizations, increasing output, yield, and production speed can minimize costs and enable industrial-scale production. In addition, the optimization of fermentation processes and product purification techniques is also an essential aspect. An efficient fermentation process can further increase the production rate and stability, while cost-effective separation and purification techniques also affect the production cost of the final product.

5 The Future of Biomanufacturing Driven by Synthetic Biology: Synthetic biology is a field that various countries are focusing on developing. The U.S. Senate passed the United States Innovation and Competition Act of 2021, and in 2022, Biden issued an executive order to launch the “**Biotechnology and Biomanufacturing Initiative**.” Our country attaches great importance to the development of synthetic biology and biomanufacturing. During the 13th and 14th Five-Year Plans, key initiatives on \"synthetic biology\" and \"green biomanufacturing\" were launched successively, which effectively promoted the advancement of these fields in our country and led to a series of original achievements. In the field of fine chemicals, thanks to its strong fermentation industry infrastructure, China is already superior to the United States in terms of product variety and cost; however, the number of available products remains limited and there is significant homogenization, which leads to competitive pressure. In the field of bulk chemicals, our country also lacks iconic products. Globally, there are only a few iconic products in the category of bulk chemicals, mainly because oil-based bulk chemicals are cheaper and require more advanced underlying technologies for development. Although biomanufacturing in our country has made significant progress in recent years, its fundamental sciences and underlying technologies still face many major challenges. Biomanufacturing involves interdisciplinary collaboration across various fields, including biology, chemistry, engineering, and computational science. Firstly, the core technologies of biomanufacturing, such as synthetic biology, metabolic engineering, and gene editing techniques, are still in the process of continuous development and improvement. Although there are already some successful application cases, technical challenges remain in areas such as the biosynthesis of bulk chemicals, the construction of cell factories, and the optimization of complex fermentation processes. For example, how to rapidly obtain efficient catalytic and regulatory elements, how to design and optimize metabolic pathways to improve conversion rates, and how to enhance the stability and yield of microorganisms in industrial production. Against this backdrop, increasing funding and strengthening the research team is particularly crucial. On the other hand, overcoming these technical challenges requires not only breakthroughs in fundamental research but also the integration and innovation of technologies. This requires a collaborative effort among the government, enterprises, and research institutions to continuously increase financial support and policy guidance for the field of biomanufacturing. At the same time, cultivating and attracting more high-level talents with interdisciplinary backgrounds is key to driving the continuous development of this field. For a long time, research and development efforts in biomanufacturing have been concentrated in a few large companies and research institutions. However, if a company wants to gain an advantage in global competition, it must continue to invest in this field. This includes not only financial investment but also efforts to strengthen talent development, the establishment of innovation platforms, and the deep integration of industry, academia, and research. The government and the industry should further improve relevant policies, encourage enterprises to increase their R&D efforts, and promote close cooperation between enterprises, universities, and research institutions to jointly overcome technical challenges. In the future, producing bulk chemicals using synthetic biology will face increasingly complex technical and market challenges; therefore, it is necessary to strengthen top-level design and strategic planning to clarify the approach to development, determining what to pursue and what to avoid. When selecting products synthesized biologically, priority should be given to those chemicals for which chemical synthesis involves long pathways, causes severe environmental pollution, requires harsh production conditions, and is costly ； Since biomanufacturing can carry out complex transformations within microbial cells, reducing the need for steps such as the separation and purification of intermediates, it holds promise as a more green and sustainable alternative. With continuous advances in basic science and underlying technologies, biomanufacturing is breaking through the limitations of chemical synthesis for bulk chemicals, which are characterized by simple production processes and fierce cost competition, thereby gradually expanding its market share. However, with the advent of the post-oil era, the continuous decline in crude oil prices has also had a profound impact on the competitiveness of bio-based products. It is expected that in the future, crude oil prices may remain around $40 per barrel for an extended period; the \"tolerance period\" for bio-based products is shrinking rapidly, and there is also a situation where oil and bio-based products must coexist over the long term. With the integrated development of synthetic biology, metabolic engineering, and AI technology, the cost of biomanufacturing will continue to decline, while its efficiency will keep increasing. Building intelligent and sustainable biomanufacturing systems will jointly push biomanufacturing to new heights, providing solid support for the green transformation of the global chemical industry. About the author: Shen Xiaolin, professor at Beijing University of Chemical Technology. The main research areas are synthetic biology and metabolic engineering. Yuan Qipeng is the deputy director and professor at the National Key Laboratory of Efficient Utilization of Chemical Resources at Beijing University of Chemical Technology. The main research areas are biochemical engineering and synthetic biology.

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