Overview

Myocarditis cases have increased following the COVID-19 pandemic, posing serious public health challenges. Traditional Chinese medicine, especially Salvia miltiorrhiza (Danshen), has shown potential in treating cardiovascular diseases through its active compounds, such as tanshinone and carnosic acid. However, traditional extraction methods are resource-intensive, costly, and time-consuming. To address this, we engineered Saccharomyces cerevisiae to efficiently produce tanshinone and carnosic acid via its MVA pathway, offering a sustainable and scalable alternative. Our project contributes to SDG 3 (Good Health and Well-being), SDG 12 (Responsible Consumption and Production), and SDG 15 (Life on Land). We have engaged some stakeholders, such as Chinese medicine researchers and biotechnology experts, to refine our project and ensure its future scalability and impact on sustainable drug production.

Stakeholder/Activity	Interaction/Feedback	Related SDGs
Dr. Jiang Qi from Department of Cardiovascular Medicine, The First People's Hospital of Changzhou, China	Shared insights on the role of tanshinones in treating myocarditis, emphasizing its potential to improve coronary blood flow and heart function.	SDG 3
Dr. Guo Juan, a researcher from National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences	Highlighted the advantages of using Saccharomyces cerevisiae for production, such as reduced environmental impact and more consistent quality.	SDG 12
Dr. Hu Yating, a professor engaged in research on synthetic biotechnology and biosynthesis of active ingredients in microbial Chinese medicine	Key insights into the biosynthesis of herbal medicines are presented, and it is shown that microbial synthesis of herbal compounds can minimize ecological impacts by avoiding wastage of plant material and land resources.	SDG 12, SDG 15
Dr. Sun Fengjun from Chinese Society of Pharmacology	Emphasized the importance of integrating traditional Chinese medicine characteristics with modern biotechnological approaches and noted the need to utilize animal experiments to verify biosafety.	SDG 3, SDG 12
Visit to Lu Youren Traditional Chinese Medicine Museum in Deqing	The visit provided insights into the origins, applications, and cultural significance of various medicinal plants, fostering a deeper understanding of their use in traditional Chinese medicine.	SDG 3, SDG 15
Visit to the Medicinal Plant Hall, Shanghai Chenshan Botanical Garden	Specifically observed Salvia miltiorrhiza (Danshen) during the visit. Enhanced the understanding of the ecological and sustainable aspects of medicinal plant cultivation and the importance of preserving biodiversity.	SDG 3, SDG 15
Educational Activities	Theme Activity on Human Health and Sustainability: Introduced the cardiovascular benefits of Salvia miltiorrhiza (Danshen) and highlighted the advantages of biosynthesizing tanshinone, explaining the sustainability and efficiency of this method compared to traditional extraction from plants, to further emphasize the importance of conservation of herbal plant resources. Community Health Talk: Conducted an informative session on preventing cardiovascular diseases among the elders and some cardiovascular disease patients, distributing posters to raise awareness about healthy lifestyles and the importance of early prevention.	SDG 3, SDG 12, SDG 15

Biosynthesis of Tanshinones and Carnosic Acid: A Pathway to SDGs

Our project aligns closely with the 2030 Agenda for Sustainable Development, specifically contributing to the achievement of several SDGs. WHO has always been concerned about the role of traditional medicine, salvia miltiorrhiza as a kind of traditional Chinese herbal medicine, which we can develop to complement traditional medicine, so as to promote people's health (SDG 3) (WHO traditional medicine strategy: 2014-2023). Additionally, we prioritize eco-friendly biosynthesis methods to minimize environmental impact and ensure sustainable use of resources, and we reduce the need for the extraction of medicinal plants such as salvia miltiorrhiza (SDG 12) (SDG 15) (United Nations, 2030 Agenda for Sustainable Development).

Our sustainable salvia miltiorrhiza cultivation project:

• Promotes SDG3 - Good Health and Well-being by biosynthesis producing high-quality, organic salvia miltiorrhiza that supports traditional medicine and enhances public health worldwide.
• Facilitates SDG12 - Responsible Consumption and Production by adopting eco-friendly farming practices that minimize environmental impact and ensure sustainable resource use in the cultivation of salvia miltiorrhiza.
• Safeguards SDG15 - Life on Land by preserving biodiversity and protecting ecosystems where danshen grows, contributing to the conservation of terrestrial habitats and the sustainable development of these areas.

Key Stakeholders

Cardiologist

Mr. Jiang Qi

Stakeholder Role: Dr. Qi Jiang is a leading cardiovascular expert with extensive experience in cardiovascular treatment and prevention. Also, as the head of the COVID-19 ward, he has a deep understanding of COVID-19 and its complications.

Feedback: He shared his experiences from the US and China, emphasizing the need for deep understanding of COVID-19 and its sequelae, such as palpitations and chest tightness commonly seen in long COVID patients. He discussed the role of Tanshinone in treating myocarditis, suggesting it improves myocardial ischemia and coronary blood flow, potentially through anti-inflammatory or infection improvement mechanisms. He also highlighted the importance of studying Tanshinone's mechanism in myocarditis, focusing on its potential benefits for managing inflammation and improving coronary circulation. His feedback helped us understand the potential of tanshinone in the treatment of myocarditis, indicating that our project's commitment to the synthesis of salvia miltiorrhizae is beneficial for improving human health.

Chinese Medicine Expert

Mrs. Guo Juan (Third from the left)

Stakeholder Role: Dr. Guo is a significant expert in traditional Chinese medicine and molecular pharmacognosy, with extensive experience in the synthesis pathways of tanshinone. Her insights into the challenges and potential solutions for direct synthesis are crucial.

Feedback: Dr. Guo compared the MEP pathway in Saccharomyces cerevisiae with that in plants, highlighting that yeast must enhance its upstream pathways for tanshinone production. She noted no particular advantage of the yeast MEP pathway over the plant pathway but emphasized the significant advantages of using yeast for tanshinone synthesis, including eliminating the need for cultivation, avoiding environmental impacts, and achieving uniform product quality. She acknowledged the project's potential despite the challenges posed by the incompletely resolved synthesis pathway, suggesting focusing on synthesizing tanshinone precursors as an initial step.

Synthetic Biologist

Mrs. Hu Yating (Third from the right)

Stakeholder Role: Dr. Hu is an expert in synthetic biology and biosynthesis of plant-derived active ingredients, with insights into enhancing production efficiency and purity of herbal medicines through metabolic engineering. Her perspectives on reducing resource waste and environmental impact are crucial for sustainable production methods.

Feedback: She highlighted successful cases of heterologous synthesis of plant-derived active ingredients via synthetic biology, noting Artemisinin and Taxol as prominent examples. To improve production efficiency and purity, strategies include overexpressing upstream pathways, eliminating competing pathways, and enhancing enzyme activity. Microbial synthesis of herbal components reduces plant resource waste and ecological damage by focusing on desired compounds without producing unnecessary byproducts, conserving land resources.

Pharmaceuticist

Mr. Sun Fengjun

Stakeholder Role: Dr. Sun is an expert in pharmacy with extensive experience in clinical pharmacy training and research on cardiac diseases, particularly myocarditis. His insights into the intersection of traditional Chinese medicine and new biotechnologies are crucial for advancing treatment options for post-COVID myocarditis. He also stressed that tanshinones must go through a series of clinical tests through animal experiments.

Feedback: Dr. Sun supports integrating traditional Chinese medicine with modern biotechnology, citing network pharmacology and novel drug target databases as beneficial for discovering new treatments. He views traditional Chinese medicine, including Salvia miltiorrhiza and its active component, as having potential therapeutic benefits for myocarditis through anti-inflammatory, immunomodulatory, antioxidant, anti-fibrotic, and cardioprotective effects, though more clinical studies are needed to confirm their safety and efficacy. To validate tanshinone's effectiveness, animal models of myocarditis would be used, followed by rigorous clinical trials from Phase I to Phase III, regulatory approval, and ongoing post-marketing surveillance.

Public Activities

In order to raise public awareness of the sustainable impact of our project, we have carried out a series of promotional activities, including an activity on the theme of "Human Health and Sustainable Development", lectures on the theme of "Cardiovascular Disease Prevention", and campus discussions on the theme of "Biodiversity Protection".

"Human Health & Sustainable Development" theme acivity, successfully showcased the advantages of biosynthetic Danshen-based medications over direct extraction from plants, highlighting their eco-friendliness. Through hands-on activities crafting traditional Chinese medicine sachets, we educated the public on the benefits of reducing the exploitation of medicinal plants, thereby contributing to biodiversity conservation and advancing our efforts towards achieving the SDG12, 15.

Our community outreach activity, centered on the theme "Cardiovascular Disease Prevention", made a significant impact by raising awareness among seniors and individuals with cardiovascular conditions. By elucidating the dire threats posed by these diseases and outlining practical prevention strategies, we empowered participants with the knowledge to safeguard their health. Furthermore, the distribution of visually appealing posters outlining preventive measures facilitated wider dissemination of vital information, making it more accessible and memorable. This initiative aligns seamlessly with SDG 3.

Our campus-based roundtable discussion, centered on the theme "Biodiversity Protection", fostered insightful conversations on minimizing environmental pollution and fostering resource conservation in the contexts of herbal medicine extraction and biopharmaceutical production. We emphasized the need for collaborative efforts to preserve ecosystems, sustainably manage natural resources, and plant degradation prevention, thereby contributing to SDG 15.

Impact of Our Project

Building on the feedback from stakeholders and community members, our project directly addresses the rising incidence of myocarditis post-COVID-19 by harnessing the therapeutic potential of Salvia miltiorrhiza (Danshen) through innovative biosynthesis methods. Our engineered Saccharomyces cerevisiae produces key active compounds, such as tanshinone and carnosic acid, effectively combating cardiovascular diseases while minimizing resource depletion associated with traditional extraction methods.

Key Outcomes

1. Enhanced Production Efficiency

Our biosynthesis approach reduces the reliance on traditional extraction from Salvia miltiorrhiza (Danshen), which is resource-intensive and time-consuming. By employing synthetic biology techniques, we achieved a scalable and sustainable method for producing tanshinone and carnosic acid, addressing the growing demand for effective cardiovascular treatments.

2. Public Health Benefits

By developing a more efficient and cost-effective method to produce cardiovascular therapeutics, our project directly contributes to SDG 3 (Good Health and Well-being). The availability of affordable treatments can significantly improve health outcomes for patients suffering from myocarditis and other related conditions.

3. Sustainability in Drug Production

The project aligns with sustainable practices by minimizing ecological impacts associated with plant cultivation and extraction. This reduction in resource consumption and waste generation supports a circular economy in the pharmaceutical industry, crucial for SDG 12 (Responsible Consumption and Production).

4. Biodiversity Conservation

Our project emphasizes the importance of conserving natural resources, particularly Salvia miltiorrhiza (Danshen). By reducing the need for extensive cultivation of this medicinal plant, we contribute to SDG 15 (Life on Land) by protecting biodiversity and promoting sustainable land use practices.

5. Community Engagement and Education

Through various educational activities, such as community health talks and workshops on traditional Chinese medicine, we raise awareness about the sustainable use of natural resources and the importance of preserving medicinal plants. This community involvement fosters a greater understanding of health and environmental issues, aligning with our goals to promote SDG 3, 12, and 15.

Contributions to Sustainable Development Goals (SDGs)

SDG 3: Good Health and Well-being

3.8 Achieve universal health coverage, including financial risk protection, access to quality essential health-care services and access to safe, effective, quality and affordable essential medicines and vaccines for all.

Our biosynthesis approach provides a more cost-effective and scalable production method for essential medicines, particularly for cardiovascular conditions. Traditional extraction methods for Salvia miltiorrhiza are expensive and environmentally taxing, making them less accessible to lower-income populations. By utilizing synthetic biology, we ensure that these medicines are affordable and widely available, contributing to universal health coverage. The project's focus on accessibility, affordability, and scalability aligns directly with SDG 3.8's goal.

SDG 12: Responsible Consumption and Production

12.2 By 2030, achieve the sustainable management and efficient use of natural resources.

Traditional methods of extracting bioactive compounds such as tanshinones and carnosic acid from Salvia miltiorrhiza are resource-intensive, often requiring extensive land use, water consumption, and energy for cultivation, harvesting, and extraction. By leveraging synthetic biology and engineering Saccharomyces cerevisiae to biosynthesize these compounds, our project offers a sustainable alternative that drastically reduces the need for natural resources. This process not only minimizes the environmental burden but also increases production efficiency. As a result, we contribute to the sustainable management of land and water resources, aligning with the goal of optimizing natural resource use while ensuring the long-term availability of essential medicinal compounds.

12.5 By 2030, substantially reduce waste generation through prevention, reduction, recycling and reuse.

The traditional extraction of bioactive compounds often generates significant waste, including leftover plant biomass, solvent waste, and by-products. In contrast, our biosynthesis platform in yeast cells mitigates this issue by producing the compounds in a controlled and closed-loop system. By eliminating the need for large-scale agricultural operations and solvent-intensive extraction methods, we drastically reduce the overall waste generated during the production process. Furthermore, yeast-based biomanufacturing systems are designed for scalability and reuse, enabling multiple production cycles without creating significant industrial or agricultural waste. This supports the transition to a more circular economy by preventing waste at its source and promoting sustainable production practices.

12.8 By 2030, ensure that people everywhere have the relevant information and awareness for sustainable development and lifestyles in harmony with nature.

Through public outreach and education, our project promotes awareness of sustainable biomanufacturing and its environmental advantages over traditional methods. Our engagement with communities and scientific outreach activities highlights the need for sustainable alternatives in medicine production. By educating the public about the environmental impacts of traditional plant-based drug production and introducing biosynthetic solutions, we encourage more informed choices and a lifestyle in harmony with nature. This aspect of our project contributes to SDG 12.8 by spreading knowledge and fostering a culture of sustainability.

SDG 15: Life on Land

15.4 By 2030, ensure the conservation of mountain ecosystems, including their biodiversity, in order to enhance their capacity to provide benefits that are essential for sustainable development.

Salvia miltiorrhiza, commonly used in traditional medicine, is often cultivated in mountainous regions, leading to ecological pressures due to overharvesting. This threatens not only the plant population but also the broader biodiversity of these mountain ecosystems. By using synthetic biology to produce tanshinones and carnosic acid in yeast, our project reduces the demand for wild-harvested Salvia, allowing mountain ecosystems to recover and flourish. This biotechnological solution directly contributes to the conservation of these regions by lessening the need for intensive plant cultivation, which in turn preserves the biodiversity and ecological balance essential for sustainable development.

Take urgent and significant action to reduce the degradation of natural habitats, halt the loss of biodiversity and, by 2020, protect and prevent the extinction of threatened species.

The overharvesting of medicinal plants like Salvia miltiorrhiza for traditional extraction methods has led to habitat degradation and a decline in biodiversity. Our biosynthetic platform alleviates the strain on natural populations of these plants, significantly reducing the need for their cultivation and extraction. By shifting production from natural ecosystems to controlled laboratory environments, we help protect threatened species and prevent further habitat destruction. This action directly contributes to the global efforts to halt biodiversity loss and prevent the extinction of species that are vital to ecosystem health.

Associated Benefits

Overall, our project contributes to multiple UN Sustainable Development Goals, including SDG 3 (Good Health and Well-being), SDG 12 (Responsible Consumption and Production), and SDG 15 (Life on Land). Our innovative biosynthesis approach not only addresses urgent health needs related to myocarditis but also contributes to broader environmental and sustainability goals. By leveraging synthetic biology to produce tanshinones and salvianolic acids, we reduce environmental impact, promote responsible resource use, and enhance access to critical medicines. This integrated approach addresses public health, ecological sustainability, and economic viability, demonstrating the broad impact of our project on sustainable development and global health.

Plans

Regulatory Alignment

This project adheres to Chinese and international regulations on biosafety, drug production, and environmental protection:

1. Biosecurity Law of the People's Republic of China: Ensures the safety of genetic engineering practices used in yeast recombinant strain development, in compliance with national biosafety standards.
2. Drug Administration Law of the People's Republic of China (2019 Revision): Governs the approval and quality standards for drug production, ensuring that biosynthesized tanshinones and carnosic acid meet regulatory requirements for drug development.
3. Plans for the Conservation and Development of Chinese Medicinal Materials (2015-2020): Encourages the protection of endangered medicinal plants, promoting sustainable methods like synthetic biology to reduce overharvesting of natural resources.
4. World Health Organization: Ensures international compliance for drug safety, efficacy, and production practices in line with global pharmaceutical regulations.
5. Environmental Protection Law of the People's Republic of China (2014 Revision): Aligns with China's broader goals of reducing environmental impact and promoting sustainability in industrial processes, including the reduction of waste and resource use during the biosynthetic production of active compounds.

Regulatory Alignment

This project adheres to Chinese and international regulations on biosafety, drug production, and environmental protection:

1. Biosecurity Law of the People's Republic of China: Ensures the safety of genetic engineering practices used in yeast recombinant strain development, in compliance with national biosafety standards.
2. Drug Administration Law of the People's Republic of China (2019 Revision): Governs the approval and quality standards for drug production, ensuring that biosynthesized tanshinones and carnosic acid meet regulatory requirements for drug development.
3. Plans for the Conservation and Development of Chinese Medicinal Materials (2015-2020): Encourages the protection of endangered medicinal plants, promoting sustainable methods like synthetic biology to reduce overharvesting of natural resources.
4. World Health Organization: Ensures international compliance for drug safety, efficacy, and production practices in line with global pharmaceutical regulations.
5. Environmental Protection Law of the People's Republic of China (2014 Revision): Aligns with China's broader goals of reducing environmental impact and promoting sustainability in industrial processes, including the reduction of waste and resource use during the biosynthetic production of active compounds.

Assessment Methods

To ensure the efficacy and sustainability of our project, we define the following long-term objectives over a 5-year period. These objectives are aligned with China’s green development policies and global sustainability goals. Progress will be evaluated through the following methods:

• Synthesis Efficiency Monitoring: Quarterly assessments of tanshinone and carnosic acid production efficiency, aiming to improve synthetic yield by 10% within the first year.
• Environmental Impact Assessments: Regular evaluations of waste by-products from the biosynthesis process, ensuring minimal environmental disruption and alignment with China's environmental protection standards.
• Drug Efficacy and Safety Testing: Conduct ongoing tests to ensure the biosynthesized compounds meet both Chinese and WHO safety and efficacy standards for pharmaceuticals.

Goals

• Short-term (1 year): Complete initial development and testing of the Saccharomyces cerevisiae platform for tanshinone and carnosic acid production, aiming for a 10% increase in synthesis efficiency. Ensure compliance with biosafety and drug regulations, completing the necessary safety assessments.
• Medium-term (2-3 years): Begin implementation in commercial production settings, achieving a 20%-30% increase in yield and a significant reduction in the extraction of natural Salvia resources. Expand regulatory compliance to include drug registration processes under Drug Administration Law of the People's Republic of China.
• Long-term (4-5 years): Achieve widespread adoption of the biosynthesis platform, with a target of reducing natural Salvia harvesting by 40% and increasing sustainable drug production capacity by 50%. Ensure international regulatory approval for the use of these biosynthesized compounds in global markets.

Implementation Phases

• Phase 1: Strain development and validation of Saccharomyces cerevisiae for efficient tanshinone and carnosic acid production. Compliance with the Biosecurity Law of the People's Republic of China will be ensured before progressing to larger-scale testing.
• Phase 2: Conduct small-scale trials in controlled lab settings. Perform safety evaluations in accordance with the Drug Administration Law and WHO guidelines. Obtain relevant certificates for moving to commercial-scale production.
• Phase 3: Apply for approval under China's drug and biosafety regulations to begin large-scale production and commercial use. Ongoing environmental assessments will be conducted to ensure minimal ecological impact.
• Phase 4: Expand production to full-scale implementation in commercial pharmaceutical applications. Continue monitoring biosynthesis efficiency and environmental impact, adjusting the process for optimization.

Monitoring Schedule

• Quarterly Assessments: Monitor production efficiency, waste output, and compliance with safety and environmental regulations every three months.
• Annual Reports: Summarize yearly progress, highlighting improvements in biosynthesis yields, reductions in natural resource extraction, and overall environmental impact. Adjust project strategies based on these evaluations.
• 5-Year Evaluations: Conduct a comprehensive assessment at the end of the 5-year period to determine whether the project has met its sustainability, regulatory, and production goals.

Possible Barriers and Strategies

• Technical Challenges: Collaborate with academic institutions and biotech companies to address any strain engineering challenges and improve biosynthetic efficiency.
• Regulatory Compliance: Work closely with Chinese and international regulatory bodies to ensure timely approval of the biosynthesized compounds for pharmaceutical use.
• Cost Management: Secure government funding and subsidies for biotechnology development under China's green technology initiatives, ensuring long-term financial sustainability.
• Market Acceptance: Promote awareness of the benefits of biosynthesized pharmaceuticals through public education campaigns, emphasizing environmental sustainability and cost-effectiveness.

References

• WHO: Traditional Medicine - https://www.who.int/news-room/questions-and-answers/item/traditional-medicine
• WHO: WHO Traditional Medicine Strategy 2014-2023 - https://www.who.int/publications/i/item/9789241506096
• Biosecurity Law of the People's Republic of China - https://leap.unep.org/en/countries/cn/national-legislation/biosecurity-law-peoples-republic-china
• Drug Administration Law of the People's Republic of China (2019 Revision) - https://www.nmpa.gov.cn/xxgk/fgwj/flxzhfg/20190827083801685.html
• Plans for the Conservation and Development of Chinese Medicinal Materials (2015-2020) - https://www.hbyxjzcg.cn/policy/show587.html
• WHO: Medicines Good Manufacturing Practices - https://www.who.int/news-room/questions-and-answers/item/medicines-good-manufacturing-processes
• Environmental Protection Law of the People's Republic of China (2014 Revision) - https://www.mee.gov.cn/ywgz/fgbz/fl/201404/t20140425_271040.shtml