Overview

To clarify the relevance and applicability of our project in the real world, we engaged with numerous academic and clinical experts, as well as individuals with personal experiences. Our goal was to understand the severity of long COVID-induced myocarditis, explore potential treatment options, and evaluate the societal acceptance of using traditional Chinese medicine (TCM) compounds produced through synthetic biology. Through surveys, interviews, and literature reviews, we gathered valuable insights that guided our project design and implementation.

Introduction

Our project is inspired by the growing concern over the long-term health effects of COVID-19. Since the outbreak in 2019, long-term sequelae such as myocarditis have emerged as significant public health issues. A study published in the Journal of the American Medical Association found that 6.2% of patients still experienced persistent symptoms three months post-infection, and 0.9% continued to live with long COVID one year later [1]. As more patients exhibit ongoing symptoms, including inflammation associated with myocarditis, there is an urgent need for new treatment strategies. To further investigate the current situation, we communicated with relevant stakeholders, including public, academic experts, clinical professionals, etc.

1. Public Survey

Our public survey revealed that long-term COVID-19 sequelae remain common among those who have recovered. Data indicates that myocarditis is a relatively severe sequela requiring medical intervention. There is still a need to enhance awareness of COVID-19 sequelae for timely identification and treatment. Based on the survey results, we plan to raise public awareness of COVID-19 sequelae and myocarditis through public education and publicity activities.

Questionnaire number: 919

Results and takeaways:

• 63.33% of respondents are aware that myocarditis is a sequela of COVID-19.
• 88.34% experienced adverse COVID-19 sequelae within four to twelve weeks post-recovery.
• 10.21% reported developing myocarditis post-recovery, requiring immediate medical attention.

2. Severity of Myocarditis

Dr. Jiang noted that most COVID-19 patients present with symptoms such as palpitations and chest tightness, indicating these symptoms are common. Some patients develop myocarditis after infection, with severe symptoms necessitating hospitalization.

Dr. Jiang Qi
Previously involved in COVID-19 prevention both domestically and internationally, currently a postdoctoral researcher at Massachusetts General Hospital, Harvard Medical School, and a committee member of the Jiangsu Alliance of the Chinese Heart Alliance for cardiovascular disease prevention and rehabilitation.

Key Points:

• Most patients present with symptoms like palpitations and chest tightness.
• Some patients develop myocarditis, with severe cases requiring hospitalization.
• Increased cardiovascular disease risk post-recovery may relate to chronic inflammation, endothelial dysfunction, and a hypercoagulable state.

3. Correlation between Myocarditis and COVID-19

Interviews with Mr. Lu, Mr. Peng, and Mr. Sun revealed that while there is insufficient clinical evidence to definitively link COVID-19 with the onset of myocarditis, an excessive immune response following infection can lead to systemic inflammation that may affect the heart, causing myocardial damage and myocarditis.

Mr. Lu Xuan
Former cardiologist, currently researching animal models.

Feedback:
While definitive clinical evidence is lacking, there is a theoretical link between COVID-19 and myocarditis due to excessive immune responses causing systemic inflammation.

Mr. Peng Jun
Chief physician in the cardiology department at the First People’s Hospital of Xiaoshan.

Feedback:

• Myocarditis arises from inflammation and edema of myocardial cells post-viral infection, leading to arrhythmias and heart failure; common viruses include parvovirus and coxsackievirus, which have confirmed receptors on myocardial cells.
• The ability of the COVID-19 virus to cause similar damage remains unproven, but there is a necessary correlation between myocarditis and COVID-19.

Mr. Sun Fengjun
Deputy Director of the Pharmacy Department at the First Affiliated Hospital of the Army Medical University, MD.

Feedback:

• Since the pandemic, most myocarditis patients have a history of COVID-19.
• Possible causes include:
  • a) direct invasion of myocardial cells by the virus;
  • b) an inflammatory immune response affecting myocardial tissue;
  • c) genetic material from the virus interfering with myocardial cell function;
  • d) abnormal immune responses post-infection leading to myocarditis.

4. Focus on Traditional Chinese Medicine

Inspired by Professor Tu Youyou's groundbreaking discovery of artemisinin, we are exploring the extraction of relevant substances from traditional Chinese medicine to treat myocarditis. Synthesizing the following interviews and tours, we focused our final research goal on the traditional Chinese medicine, Salvia miltiorrhiza, which contains relevant components with anti-inflammatory and antioxidant effects, and has a therapeutic effect on myocarditis.

Mr. Zhang Qinchang
PhD student at Nanjing University of Chinese Medicine, focusing on Chinese medicine in cancer research.

Feedback:

• Chinese medicine can effectively treat myocarditis-related diseases using strategies such as clearing heat, detoxifying, nourishing the heart, and promoting blood circulation.
• Traditional Chinese medicines like Shengmai Decoction and Xinsuo Capsules have been used in the treatment of viral myocarditis.

Traditional Chinese Medicine Museum

• At the Traditional Chinese Medicine Museum, we can explore ancient medical texts, preserve herbal specimens, and displays of traditional pharmaceutical techniques, gaining a deeper understanding of the cultural significance of Chinese Medicine.
• As modern society increasingly prioritizes health, the efficacy and value of traditional Chinese medicine have garnered wider recognition. This is especially true considering global health crises like the COVID-19 pandemic, which has drawn significant attention to the preventive and therapeutic roles of Chinese medicine.
• The active components of many Chinese medicinal herbs are gradually being unveiled through current research, particularly their anti-inflammatory and antiviral properties.

Dr. Feng
Director of Chenshan Botanical Garden

Feedback and Recommendations:

• During our visit to Chenshan Botanical Garden, we discovered an abundance of Danshen growing in the garden, aligning perfectly with our goal of developing treatments for myocarditis.
• Dr. Feng highlighted that Danshen is an important Chinese medicinal herb known for its anti-inflammatory, antioxidant, and blood circulation-enhancing properties. Its active compounds, such as Tanshinones and Tanshinones IIA, have been shown to positively impact cardiovascular health, especially demonstrating promising potential in the prevention and treatment of myocarditis.

5. Therapeutic Potential of Tanshinones and Carnosic Acid

Research shows that Danshen root possesses anti-inflammatory, anti-tumor, antibacterial, and neuroprotective properties, with compounds like Carnosic acid and Tanshinones being widely used for inflammation-related diseases [2]. Discussions with Ms. Guo indicated that components within Danshen exhibit anti-inflammatory effects, showing promise in treating myocarditis.

Ms. Guo Juan
Researcher at the Chinese Academy of Chinese Medical Sciences, Chinese Medical Resource Center.

Feedback and Suggestions:

• Confirmed that Danshen's components (e.g., Tanshinones and Carnosic acid) have anti-inflammatory properties, indicating therapeutic potential for myocarditis.
• There is currently no clear synthesis pathway for Tanshinones, necessitating clarification of specific intermediate pathways. However, synthesis can begin with known precursors.
• Suggests rigorous scientific methods to verify the therapeutic effects of Tanshinones and Carnosic acid, including clinical trials with control groups and patient follow-ups to obtain robust conclusions.

6. Confirming the Basic Route and Advantages

Literature review reveals limitations in current plant extraction techniques, including high costs, unstable raw material supply, low product purity, and environmental damage. (more details). Our solution focuses on the biosynthesis of Tanshinones and Carnosic acid using yeast. Professor Hu recognized our technological route as a compelling sustainable solution for the future of drug development, in line with Sustainable Goal 12 (Responsible Consumption and Production). In addition, relevant constructive suggestions were made regarding the safety aspects of our project, which helped to improve the SDGs.

Professor Hu Yating
Professor at Capital Medical University, member of the TCM Resource and Molecular Pharmacology team, specializing in synthetic biology and microbial biosynthesis of TCM active ingredients.

Feedback and Suggestions:

• Endorsed the concept of synthesizing Tanshinones and Carnosic acid in yeast.
• Compared to traditional plant extraction, this method is more sustainable, cost-effective, and ensures higher purity and consistency. There is potential for increased yield with minimal environmental impact. Consistent with SDG 12.2 Achieve sustainable management and efficient use of natural resources. (See SDG text for details).
• Emphasized the need for robust biosafety measures, including technology to prevent data breaches.

7. Integrating Feedback into Project Design

(1) Addressing Technical Challenges

• From the investigation and interviews, we recognized the limitations of plant extraction, including high costs, unstable supply, low purity, and environmental damage.
• So we decided to engineer yeast for the biosynthesis of Tanshinones and Carnosic acid, providing a sustainable and scalable solution.

(2) Considering Ethical, Legal, and Social Implications (ELSI)

• Acknowledge public concerns about GMOs and synthetic biology.
• Plan educational outreach to educate the public about the safety and benefits of our approaches.
• Ensure compliance with laws and regulations governing GMO research and production.

(3) Biosafety Consideration

Biosafety protocols have been carefully evaluated and integrated to ensure the safe handling and production of genetically modified organisms in line with industry standards.

8. Future Plans

• Enhancing Product Yield:
• Suggest modifying yeast upstream pathways to produce the desired metabolites while minimizing environmental impact.
• Advancing to Clinical Applications:
• i. Establish animal models
• ii. Design groupings
• iii. Determine dosing and administration
• iv. Monitor and record physiological indicators in animals
• v. Conduct pathological analysis post-experimentation
• vi. Phase III clinical trials
• vii. Analyze clinical data and regulatory submissions
• viii. Market release and testing
• Alignment with Sustainable Development Goals:
• Our project improves patient health and addresses pressing global health issues by developing effective treatments for myocarditis caused by COVID-19, which is in line with Goal 3 (Good Health and Well-Being).
• By sustainably biosynthesizing bioactive compounds such as tanshinone and carnosic acid in engineered yeast, we reduce dependence on traditional plant extraction, reduce environmental impact, and promote resource efficiency, which is in line with Goal 12 (Responsible Consumption and Production).
• We reduce large-scale collection of salvia miltiorrhiza plants, protect terrestrial ecosystems and biodiversity, prevent land degradation, and support Goal 15 (Life on Land).

In the future, we will face many challenges. Drug development is a lengthy process, but we are confident that through ongoing research and collaboration, we can overcome these obstacles. Scientific advancements and technological innovations will equip us with new tools and methods to extract and synthesize active compounds more efficiently. Meanwhile, clinical trials and data analysis will help us validate efficacy and ensure safety. We look forward to providing effective solutions for the treatment of myocarditis and improving patients' quality of life soon.

References

• [1] LAKSHMI CHAKRADHAR YARLAGADDA D G, ULLASH BASAK, MANAB SENAPATI, MONALISA DAS, RAJDEEP GHOSH. Post-COVID-19 cardiovascular sequelae and myocarditis. Journal of the Association of Physicians of India, 2023, 71(6): 11-12.
• [2] 杜原景，绪万梅等. 丹参有效成分及丹参类制剂抗炎药理作用的研究进展. 药物评价研究, 2021, 44(11): 2322-2332.