Academician Ma Dawei on Synthetic Biology at VBEF 2025: No Process Is Irreplaceable—Cost and Sustainability Are Decisive

“Cost, cost, cost.” Recently, at the “2025 Global Bio-Manufacturing Conference (GBC 2025),” hosted by VCBeat and co-hosted by Dr. Fang, “cost” became the key emphasis of Ma Dawei, an academician of the Chinese Academy of Sciences.

“We have been engaged in transformation and process optimization for so many years, and our greatest insight is that no chemical transformation is irreplaceable in the manufacturing process. Ultimately, only those transformation methods that are cost-effective, readily available, environmentally friendly, safe, and easy to operate can compete in the market,” said Ma Dawei.

Chemical synthesis boasts a rich historical legacy, while synthetic biology is emerging as a rising star; each possesses its own distinct advantages.

For instance, pharmaceuticals can be regarded as the category of chemicals with the highest product value. In the early stages of drug discovery, chemical synthesis dominates due to its ability to rapidly build compound libraries, offering significant efficiency advantages. However, when transitioning to large-scale production, enzymatic catalysis technologies in synthetic biology demonstrate more pronounced advantages, as cost and environmental sustainability become the decisive factors in process selection.

However, even during the mass production phase, the advantages of synthetic biology are not absolute; it holds cost and environmental benefits only in certain fields and segments of the industrial chain. Therefore, the integration and collaborative innovation of chemical synthesis and synthetic biology may well be the current “answer.”

It is understood that synthetic biology refers to a processing approach centered on industrial biotechnology, utilizing enzymes and microbial cells in combination with chemical engineering techniques to produce target products, including bio-based materials, chemicals, and bioenergy. As a platform technology, synthetic biology plays a crucial role in biomanufacturing.

According to data from Huaan Securities, the global synthetic biology market is expected to maintain a rapid growth rate, approaching $50 billion by 2028. Meanwhile, the downstream applications of synthetic biology are diverse, with widespread adoption across numerous sectors, including healthcare, food and agriculture, chemical industry, and consumer goods.

Synthetic biology indeed offers distinct advantages in certain areas of pharmaceutical manufacturing.

Ma Dawei pointed out that, despite considerable efforts in chemical synthesis to date, the chemical production of drugs remains costly: the psychotropic drug paroxetine costs 3,000 yuan per kilogram, and the antiviral drug sofosbuvir costs 3,880 yuan per kilogram. Although tetracycline and erythromycin have more complex structures than these two drugs, their production via synthetic biology costs only 250 yuan and 400 yuan per kilogram, respectively. This is because synthetic biology enables many reactions to be combined into a “one-pot” cascade process—an approach long pursued by chemical synthesis.

Ma Dawei also cited a series of typical cases where enzymatic catalysis has been successfully applied to industrial-scale drug production, with P450 monooxygenases being the most notable—“it can be said that they are astonishing even to experts in chemical synthesis.”

According to reports, P450 oxidase can be used to synthesize a key reagent for inducing animal models of Parkinson’s disease. The annual demand for this reagent reaches hundreds of kilograms. However, its molecular structure is complex, containing three chiral centers. Conventional chemical synthesis requires at least a dozen reaction steps, whereas the adoption of P450 oxidase technology significantly simplifies the synthetic route, overcoming challenges that are difficult to address with traditional chemical methods. “Nevertheless, the speed of obtaining novel chiral compounds through synthetic biology still needs to be improved.”

“Styrene monooxygenase can be utilized in the production of the antifungal drug efinaconazole. The original chemical synthesis route was highly complex, whereas the new enzymatic catalysis process enables the direct conversion of raw materials into a high-purity target product.” Notably, the enzyme used in this process underwent 13 rounds of directed evolution, resulting in an approximately 1,680-fold increase in conversion efficiency, stated Ma Dawei.

According to Ma Dawei’s analysis, the diabetes drug sitagliptin is now being produced using aminotransferases. The key amino structure of suvorexant, a medication for insomnia, is also synthesized through aminotransferase catalysis. Rimegepant, a drug for migraine treatment, represents another typical case of aminotransferase application. Initially, the research team found that the enzymatic conversion rate was zero, with virtually no transformation occurring; however, after directed evolution, a 99% conversion rate was achieved.

Furthermore, synthetic biology approaches can address challenges related to compound sourcing, such as obtaining sufficient quantities of complex molecules for derivatization and utilizing combinatorial biosynthesis to construct libraries of complex natural products. Fully leveraging the role of synthetic biology at the early stages of drug discovery also lays the foundation for its future application in the large-scale manufacturing of pharmaceuticals.

However, the application of synthetic biology in pharmaceuticals has certain limitations and is not utilized across all fields.

Ma Dawei emphasized that when a drug truly reaches the stage of commercial-scale manufacturing, only one or two processes are likely to be decisive; ultimately, it comes down to which process offers greater manufacturing convenience and lower product costs. “Whether in biomanufacturing or chemical synthesis, the final evaluation hinges primarily on two criteria: cost and environmental sustainability.”

The case of artemisinin vividly demonstrates how cost factors ultimately determine the fate of a production process. Ma Dawei stated that while artemisinin can be regarded as a milestone achievement in chemical synthesis, it has yet to achieve commercial viability. This is primarily because the cost of cultivating Artemisia annua by farmers in Yunnan Province, China, remains approximately RMB 200 per kilogram lower than that of synthetic biology-based production. Amyris, the pioneer of synthetic biology, filed for bankruptcy in 2023 without ever witnessing a decline in Artemisia annua cultivation by Yunnan farmers.

“Moreover, more than 20 listed companies launched by the U.S. synthetic biology industry between 2006 and 2008 have all failed. Other bankrupt companies include Metabolix (PHA), BioAmber (succinic acid), and Kior (biomass-based liquid fuels), all due to uncompetitive costs; cultured meat companies are currently facing similarly low market acceptance.”

Ma Dawei analyzed that, in fact, there are few synthetic biology cases similar to the production of tetracycline and erythromycin in the pharmaceutical field, primarily because most drugs have not yet reached a stage where they can be manufactured biologically, such as morphine, artemisinin, and paclitaxel. Synthetic biology methods mainly work by mimicking nature; however, most current drugs possess non-natural structures. For instance, examining the structures of certain kinase inhibitor targeted therapies reveals many consist of linked benzene rings, making it difficult to identify enzymatic catalytic pathways for their production. Consequently, the non-natural character of drug molecules renders chemical synthesis more advantageous.

"Therefore, synthetic biology can address some drug manufacturing issues, but not the majority of them."

From this perspective, chemical synthesis and synthetic biology each have their distinct advantages and limitations depending on the scenario. Ma Dawei emphasizes that chemical synthesis and synthetic biology are not mutually exclusive competitors but rather complementary partners achieving win-win cooperation. In fact, in pharmaceutical manufacturing, these two approaches can converge and integrate with each other.

“The development trends of small-molecule drugs have led to the dominance of chemical synthesis in both drug discovery and large-scale manufacturing. There is still a long way to go in developing more efficient reactions and synthetic strategies, which represents a key direction for the future advancement of small-molecule synthetic chemistry and synthetic biology. Strengthening the integration of chemical synthesis and synthetic biology approaches can enhance synthetic efficiency.”

“Moreover, developing other types of enzymatic reactions can expand the application scope of synthetic biology in small-molecule synthesis. The integration of enzymatic catalysis and chemical synthesis represents an important trend for future development,” stated Ma Dawei.