Clinical Needs Analysis

Core Problem: Challenges in Liver Cancer Treatment

• Difficulty in early diagnosis
• Limited effectiveness of traditional treatments with high recurrence rates
• Low response rates to immunotherapy with off-target effects and immunosuppression issues

Solutions

• Interviews with oncology and hepatobiliary surgery experts at Xijing Hospital

Outcomes

• Identified high heterogeneity, immune evasion, and recurrence as major bottlenecks
• Hypothesized macrophage engineering as a potential breakthrough direction

Confronting the Global Challenge of Liver Cancer: Our iGEM Mission

Understanding the challenges in liver cancer treatment

The Daunting Reality of Cancer Today

Cancer remains one of the most formidable challenges in modern medicine. Despite advancements in technology and research, its complexity, heterogeneity, and evolving resistance to conventional therapies continue to lead to high mortality rates worldwide. The fight against cancer demands innovation, integration, and a relentless pursuit of new strategies.

This is a mission championed by leading oncology associations like the Chinese Anti-Cancer Association (CACA). Under the guidance of esteemed academics such as Professor Fan Daiming, CACA promotes a holistic "pan-cancer" approach. They emphasize that overcoming cancer requires moving beyond siloed research and embracing Integrated Medicine— combining the best of Western treatments, Traditional Chinese Medicine (TCM), nutritional support, and mental healthcare to create patient-centric solutions. This philosophy highlights a critical gap in our current arsenal: the need for more precise, effective, and integrative therapies that can address the unique challenges of specific cancers.

Focusing on the Pressing Challenge of Liver Cancer

Nowhere is this challenge more acute than in Liver Cancer, particularly Hepatocellular Carcinoma (HCC). It stands as a leading cause of cancer-related death globally, characterized by late diagnosis, high recurrence rates, and limited treatment options. The complex microenvironment of the liver and the aggressive nature of the disease make it a critical front in the war on cancer. The current standard of care often involves invasive surgeries and systemic therapies with severe side effects, underscoring an urgent need for groundbreaking, targeted interventions.

• Early detection remains problematic due to nonspecific symptoms
• Existing screening methods have limited sensitivity for early-stage tumors
• Treatment resistance develops rapidly in most patients

Our Clinical Analysis Approach

Inspired by the integrated approach of pioneers like CACA and driven by the urgent unmet needs in oncology, our iGEM team has dedicated its project to pioneering a new front in the battle against liver cancer.

We conducted in-depth interviews with oncology experts and hepatobiliary surgeons at Xijing Hospital to understand the clinical realities of liver cancer treatment. These discussions revealed that high heterogeneity, immune evasion, and recurrence are the major bottlenecks in current treatment approaches.

Our analysis confirmed that macrophage engineering represents a promising breakthrough direction, offering the potential to address these fundamental challenges through a synthetic biology approach.

Immunotherapy Feasibility

Core Questions

• Are macrophages suitable for this approach?
• How to combine with clinical practice?

Solutions

• Interviews with Xijing Hospital Expert Professor
• Focus on the connection between clinical and basic medicine

Outcomes

• The limitations of clinical treatment were clarified, and the feasibility of clinical transformation of the project was proposed.

Interview with Prof. Yongzhan Nie

Build a bridge between ' scientific research and clinical

In order to make the project research more in line with the actual clinical needs and accurately grasp the pain points and breakthrough directions in the field of liver cancer treatment, we specially interviewed Professor Nie Yongzhan, who has profound attainments in the clinical research field of liver cancer in Xijing Hospital, aiming to clarify the current clinical treatment of liver cancer from the perspective of experts. The room for improvement and provide professional guidance for the clinical application prospects of the project. During the interview, Professor Nie Yongzhan combined with rich clinical experience and cutting-edge research results to systematically sort out the key issues that still need to be broken through in the current clinical treatment of liver cancer, such as the accuracy of early diagnosis, the effectiveness of advanced treatment regimens, and the individual treatment of different patients. The shortcomings of adaptation and other aspects provide an important clinical basis for the follow-up optimization of our project. At the same time, we introduced the technical principle, core design and preliminary research ideas of the project to the professor in detail. The professor put forward valuable suggestions on how to deeply combine the project with clinical needs, which not only affirmed the potential value of the project in making up for the existing treatment shortcomings, but also gave specific guidance from the perspective of the feasibility and safety of clinical transformation, helping us to more clearly define the positioning and development prospects of the project in the clinical application of liver cancer.

The interview with Professor Nie Yongzhan has effectively built a bridge between scientific research and clinical practice for the project. On the one hand, the clinical pain points pointed out by the professor make us clear the direction that the project needs to focus on, such as the lack of accuracy in early diagnosis, and the subsequent optimization of the detection sensitivity design of the project. On the other hand, the practical suggestions on clinical transformation also help us avoid the possible risks of technology landing, so that the project research is no longer limited to laboratory theory, but more practical to promote clinical application. These specific gains not only provide a clear basis for the follow-up optimization of the project, but also let the team know more clearly how to make the research results truly serve the clinical treatment of liver cancer.

Liver-Specific Marker Screening

Core Question: How to achieve liver-specific activation?

• Find a membrane protein highly and specifically expressed in the liver as the synNotch activation signal

Solutions

• Screening antibodies using software
• Literature review of liver-specific markers

Outcomes

• Identified SLC17A2 as a candidate marker with liver-specific expression in both healthy and cancerous cells
• Verified SLC17A2 conservation across species, suitable for cross-species applications

Intelligent Protein Screening and Design Platform: Powering Precision Targeting for Liver Cancer Therapy

Identifying optimal targets for precise activation

In our project, the primary challenge was to efficiently and accurately identify liver-specific proteins suitable for targeting design from the vast proteomic landscape. Traditional screening methods are not only time-consuming and labor-intensive but also fall short in systematically evaluating the multi-dimensional characteristics of proteins. To address this, our team independently developed an intelligent protein screening and design platform that seamlessly integrates bioinformatics, artificial intelligence, and synthetic biology design—equipping our cell therapy with a "smart navigation" system.

The core strength of the platform lies in its highly integrated and intelligent architecture. First, it dynamically connects to authoritative international protein databases such as UniProt via API interfaces, building a specialized knowledge base for liver-specific proteins. Users can set flexible filtering criteria based on key attributes—such as membrane localization, tissue-specific expression levels, and transmembrane domains—enabling millisecond-level preliminary screening and significantly accelerating the process of target discovery.

More importantly, we have innovatively embedded machine learning algorithms into the protein engineering workflow. For candidate proteins identified through screening, the platform not only predicts their three-dimensional structures from amino acid sequences but also performs rational optimization of binding interfaces based on these structural insights. This means we are no longer limited to passively "selecting" natural targets; instead, we can proactively design or optimize ideal ligands with improved compatibility to the SynNotch system, higher affinity, and enhanced specificity—thereby fundamentally enhancing the precision recognition capability of our engineered macrophages.

We firmly believe that computationally empowered biology represents a critical direction for the future of synthetic biology. This platform is not only a powerful tool for advancing our project; its modular and universal design also allows it to be easily adapted for the discovery of tissue- or disease-specific proteins beyond our current focus. It fully embodies our team's commitment to interdisciplinary innovation, bridging cutting-edge computational science and life sciences, and ultimately contributing to the realization of programmable precision medicine.

synNotch-M System Design

Core Questions

• The composition of the system? Upstream and downstream genes?
• Why use synNotch? Is it feasible?

Solutions

• Interviews with immunology experts
• Focus on downstream gene selection and expression optimization

Outcomes

• Extracellular domain: scFv antibody target SLC17A2
• Downstream genes: P65 overexpression and SIRPα shRNA
• Optimized shRNA expression using miRNA processing mechanisms

SynNotch-M System Design

Engineering a precision therapeutic system

System Architecture

Designing the synNotch-M system required careful consideration of multiple components and their interactions. We consulted experts in genetics and immunology to optimize our design.

Key Components

Our final system design includes:

• Extracellular domain: scFv antibody targeting SLC17A2 for liver-specific recognition
• Intracellular domain: Gal4VP64 (GV) transcriptional activator for downstream gene expression
• Downstream genes: UAS-regulated P65 overexpression and SIRPα shRNA for therapeutic effect

Innovative shRNA Expression

We implemented an innovative approach to shRNA expression using miRNA processing mechanisms. This optimization allows for more efficient gene silencing while minimizing off-target effects.

Interview Conclusion

Through interviews with genetics and immunology experts, we have confirmed that our SynNotch system utilizes a single-chain antibody targeting SLC17A2 as the input, and delivers SIRPα RNA and P65 as downstream effectors to execute its therapeutic functions.

Function & Safety Validation

Core Question: Is the system effective and safe?

Solutions

• Interviews with Xijing Hospital Expert Professor
• Communicate with pharmaceutical and biotechnology companies to clarify the feasibility of the project.

Outcomes

• Effective control of cytokine storm
• Using paper nanoparticle delivery system to reduce costs and improve safety

Clinical landing and into the production

Interview with Prof. Sanzhong Li

This interview aimed to gather insights from frontline clinical experts regarding the current application status and key challenges of immune cell therapy in advanced liver cancer treatment. Given that cell therapies often incur substantial costs—ranging from hundreds of thousands to millions of RMB—we focused on understanding real-world patient acceptance rates and the proportion of patients compelled to forgo treatment due to financial constraints.

We further sought to clarify the composition of these high costs, analyzing the relative contributions of production, transportation, and personalized customization processes. This analysis helped evaluate the cost-effectiveness ratio and explore how to strike a balance between therapeutic efficacy and affordability—issues of significant concern to both patients and clinicians.

Safety concerns, such as cytokine release syndrome (CRS) and neurotoxicity risks, were also specifically addressed. In relation to our proposed macrophage-based immunotherapy strategy (e.g., the syn-M system), the experts provided professional advice on effectively mitigating such side effects.

Finally, we introduced our project's novel approach: using lipid nanoparticles (LNP) to deliver mRNA directly to macrophages in vivo, enabling their direct reprogramming into tumor-fighting engineered cells. This method holds promise for substantially reducing costs and enhancing treatment safety. We solicited the experts' views on the feasibility, prospects, and critical technical aspects of this strategy.

In summary, this expert interview provided critical validation for our technical pathway and offered deeper insight into the core challenges currently faced by cell-based immunotherapy, helping to clarify the potential of our innovative technology to address these pressing issues.

Interview with biotechnology company

Through interviews and site visits to biotechnology companies, we gained a deeper understanding of the complexity and rigor involved in translating research into practical applications. We specifically inquired about the clinical feasibility of Syn-M cell therapy and learned that its potential application would require a multi-stage validation process, including in vitro experiments, in vivo studies, and animal trials, to systematically evaluate its efficacy and safety before clinical implementation can be considered.

Patient-Focused Care

Core Question: Does the system meet ethical, legal, and patient needs?

Solutions

• Legal consultation for compliance
• Ethics committee interviews on challenges in cancer therapy, animal testing, and macrophage-based treatments
• Informed consent document preparation
• Patient interviews with privacy protection and emotional sensitivity

Outcomes

• Comprehensive understanding of patient needs
• Project alignment with ethical and legal standards
• Completed informed consent documentation

Patient-Focused Care

Ensuring ethical and patient-centered development

Ethical Considerations

We engaged with ethics committees to address important ethical questions surrounding our research, including:

• Challenges in cancer therapy and patient consent
• Ethical implications of animal testing in research
• Special considerations for macrophage-based treatments

Interview with Qiuju Zhang, an expert in the teaching and research section of university ethics.

Based on our interview with faculty members from the university's ethics research department, we engaged in an in-depth discussion regarding the medical ethics considerations relevant to our project. Key ethical principles emphasized include:

• Patient-Centered Approach: All research and development must prioritize patients' well-being, autonomy, and long-term interests.
• Informed Consent: Ensuring participants fully understand the purpose, procedures, potential risks, and benefits of the study.
• Privacy and Data Security: Protecting the confidentiality of patient information and genetic data in accordance with regulatory standards.
• Risk-Benefit Balance: Carefully evaluating and minimizing potential harms while maximizing therapeutic benefits.
• Equity and Accessibility: Considering how the technology can be made available to diverse populations, avoiding exacerbation of healthcare disparities.

These discussions reinforced our commitment to designing and implementing our project with a strong ethical foundation, ensuring that patient needs and values guide every stage of development.

Legal Compliance

Legal consultations ensured our project complies with all relevant regulations and guidelines for cell-based therapies and genetic engineering.

Interview with Xu Li, a psychological counseling expert from the Air Force Medical University

Cancer patients often experience significant psychological distress, such as anxiety and depression, which adversely affects their quality of life and treatment outcomes. To deeply integrate Human Practices into our project, we interviewed Professor Xu, a psychological counseling expert from the Air Force Medical University, and collaborated to develop a mindfulness-based guide—the Mindfulness Anti-Cancer · Heart-Ease Handbook—to address these psychosocial challenges:

• Expert Insight: To gain a systematic understanding of the psychological challenges faced by cancer patients and the application of mindfulness interventions through in-depth interviews with specialists. (efficacy, side effects, quality of life)
• Practical Resource Development: To compile a scientifically-grounded, accessible, and practical mindfulness guide, offering tangible psychological support to patients.
• Societal Impact: To raise public awareness about the psychosocial well-being of cancer patients, alleviate the mental burden on patients and their families, and broaden the supportive care strategies available to healthcare professionals.

Patient Engagement

We conducted interviews with liver cancer patients to understand their perspectives, needs, and concerns. These conversations were conducted with strict privacy protection and emotional sensitivity, revealing:

• Patient priorities for new treatments (efficacy, side effects, quality of life)
• Concerns about experimental therapies
• Preferences for treatment information and communication

Informed Consent Development

Based on our ethical and patient engagement work, we developed comprehensive informed consent documentation that clearly explains:

• The nature of the proposed treatment
• Potential benefits and risks
• Alternative treatment options
• Patient rights and protections

This phase ensured our project aligns with both ethical standards and patient needs.

AI-Powered CT Analysis Platform for Enhanced Liver Cancer Diagnosis

In our human practice engagements with hepatocellular carcinoma (HCC) patients, we identified a critical bottleneck in clinical diagnosis: traditional CT image analysis heavily relies on physicians' subjective judgment, leading to diagnostic variability that can impact early detection rates and treatment planning. This is particularly challenging for sub-centimeter lesions (5mm) or atypical nodules, where manual interpretation is prone to oversight due to fatigue or limited experience.

To address this, we developed an intelligent CT image analysis platform that integrates deep learning with 3D reconstruction, providing an "intelligent eye" for precise liver cancer diagnosis.

Key Features & Innovations:

• Automated Lesion Detection: Trained on multi-center clinical datasets, our deep learning model automatically detects and characterizes liver lesions, quantifying key features including size, morphology, and density.
• Multi-phase Dynamic Analysis: The platform supports automatic registration and synchronized analysis of multi-phase CT scans, generating dynamic enhancement curves to help differentiate HCC, cholangiocarcinoma, and hemangiomas based on characteristic perfusion patterns.
• 3D Surgical Planning: The system generates interactive 3D reconstructions of the liver, tumors, and vasculature. Coupled with watershed analysis, it calculates future liver remnant volume and simulates precise anatomical resections, minimizing intraoperative risks—particularly valuable for complex cases with cirrhosis or vascular variations.

We believe intelligent medical tools are crucial bridges connecting synthetic biology to clinical application. While currently optimized for liver cancer, our platform's modular architecture can be extended to other organs, potentially serving as a versatile, open-source medical imaging solution for the iGEM community and beyond.

Phase 7: Multidisciplinary Collaboration

Core Question: How to promote interdisciplinary integration and public awareness?

Solutions

• University collaborations: Interdisciplinary seminars with medical, biological, and engineering experts
• Science communication partnerships: Articles, videos, and public lectures

Outcomes

• Enhanced project visibility and societal impact
• Increased public understanding of synthetic biology applications in medicine

Multidisciplinary Collaboration

Promoting interdisciplinary integration and public awareness

University Collaborations

We organized interdisciplinary seminars bringing together experts from medicine, biology, and engineering to foster cross-disciplinary dialogue and innovation. These collaborations:

• Provided diverse perspectives on our project challenges
• Identified potential applications in other disease areas
• Facilitated knowledge exchange between academic disciplines

Collaboration with Dalian University of Technology

In collaboration with Dalian University of Technology, we co-produced a thematic podcast focusing on liver cancer knowledge dissemination and mutual iGEM project sharing. Titled "Liver Cancer Prevention and the Application of Synthetic Biology," the podcast was intentionally designed with accessibility in mind, using clear and vivid verbal descriptions to ensure content comprehension for visually impaired audiences.

The episode was structured into two main segments:

• Public Science Education: Both teams explained liver cancer risk factors, early screening methods, and preventive measures in plain language, making specialized knowledge accessible to the general public, especially those with visual impairments.
• Project Exchange: We presented our project's technical strategy and design rationale for targeting liver cancer, while DUT's team shared their innovative approaches within the same field.

This cross-university initiative not only facilitated accessible science communication through audio media but also created a platform for technical dialogue between iGEM teams, enabling interdisciplinary exchange and expanding the social impact of both projects.

Interview with An Yang, a Professor from foreign languages teaching and research office from the Air Force Medical University

To enhance the effectiveness of our project's global science communication, we engaged in a consultation with experts from the Foreign Language Teaching and Research Section. This collaboration focused on mastering the distinct English language styles required for both public outreach and formal academic presentations. Under the expert guidance, we refined key skills including the precise use of scientific terminology, the application of formal academic syntax and grammar, and strategies for compelling delivery. This process allowed us to critically evaluate and improve how we present our complex synthetic biology project, ensuring it can be clearly and engagingly communicated to a worldwide audience. This experience has significantly strengthened our capacity for international dissemination.

Societal Impact

Our outreach efforts have enhanced project visibility and societal impact by:

• Increasing public awareness of synthetic biology's potential in medicine
• Engaging stakeholders in discussions about ethical implications
• Inspiring future generations of scientists and engineers

Sign language videos

To bridge the communication gap between the deaf and hard-of-hearing community and synthetic biology knowledge, we produced a series of sign language videos focusing on key terminology essential for understanding our project. Six core concepts were selected: "Cancer, " "Liver, " "Prevention, " "Universal, " "Macrophage, " and "Early Treatment. " These terms define the disease focus, target organ, core biological mechanism, intervention goals, and unique technical advantages of our project.

The videos were developed in strict accordance with national standard sign language guidelines, with professional sign language experts involved in gesture design and review to ensure accuracy and clarity.

This initiative not only enhances the accessibility of our project content for the deaf and hard-of-hearing community but also provides reusable reference materials for other research teams and organizations, promoting inclusive science communication and aligning with iGEM's principle of "Science for All. "

Popular science handbook

To enhance the accessibility of liver cancer education and enable visually impaired individuals to independently access project-related health and scientific information, we produced a Braille version of our popular science handbook. This initiative ensures equal rights to scientific knowledge for the blind and visually impaired community.

The original handbook covers essential topics including basic knowledge of liver cancer, the application of synthetic biology in oncology, our project's core research focus, and prevention recommendations. During the Braille adaptation process, we strictly followed national Braille standards and collaborated with professional transcribers to accurately convert the content word by word. The layout was optimized for clarity and tactile recognition, with simplified language to improve comprehension.

For example, the technical approach of our project was described in straightforward Braille with a logically structured flow, allowing readers to clearly grasp the design and potential impact. Prevention guidelines were condensed into concise bullet points for easy memorization and daily practice.

This Braille handbook extends our science communication system through tactile media, filling a critical gap in accessible science education. It reflects our team's commitment to inclusivity and social responsibility, embodying iGEM's principle of "Science for Everyone " in a tangible and meaningful way.

Future Directions

Based on our multidisciplinary collaborations, we have identified several promising future directions:

• Adapting our platform technology for other cancer types
• Exploring combination therapies with existing treatments
• Developing more advanced delivery and control systems

The phase has positioned our project for maximum impact both scientifically and societally.

iGEM Human Practices - AFMU China 2025