Engineering IHP Framework

To ensure that our Human Practices work consistently embodies the Design–Build–Test–Learn (DBTL) cycle of iGEM, we developed a dedicated framework-the Engineering IHP Framework.

Building on the experience of last year's HP efforts, we designed this framework to guide our future activities in a way that is logically closed-loop and aligned with engineering principles. Throughout this year, our HP practices have been deeply integrated into this framework. The results demonstrate that this approach has significantly advanced our work and ensured that our project evolved in a systematic manner. At the same time, we hope that this framework can inspire other iGEM teams, and we warmly welcome suggestions and feedback from judges, teams, and the broader iGEM community for its further improvement.

At the core of our design lies the Problem–Solution concept. Unlike pure science communication, HP must address the real challenges faced by a project-whether current or potential, predictable or unforeseen. In our framework, every journey begins with a Problem, and the endpoint is a Solution, achieved after multiple cycles of investigation, practice, feedback, and integration.

A solution does not mean closure but rather a timely response: resolving an issue, mitigating its risks, or adapting our project direction when necessary.

• The Engineering IHP Cycle
• Investigation – "No Investigation, no right to speak."

  Corresponding to Design, this stage builds on preparation, literature review, and authoritative sources to provide the theoretical basis for our project.

❗Expert interviews could fit here, but in our framework they are placed under Practices to stress their interactive nature.

• Practices – "Practice is the sole criterion for testing truth."

  Corresponding to Build, this stage centers on direct engagement. First-hand interactions provide unique insights beyond desk research.

• Feedback – "The most valuable thing you can get from others is not praise, but feedback."

  Corresponding to Test, this stage collects responses to our practices, assessing effectiveness and exposing potential gaps or unforeseen issues.

• Integration – "Human Practices are about integrating feedback to make your project responsible and good for the world."

  Corresponding to Learn, this stage incorporates feedback into our project, leading to design refinements, new research directions, or even shifts in guiding philosophy.

Completing one loop does not mean the problem is solved. Instead, three outcomes are possible:

1. The problem remains partly unresolved, requiring further iteration;
2. A new, unexpected issue emerges, prompting us to decide whether to pursue it;
3. The problem is sufficiently addressed, allowing integration into the broader project.

Each cycle, regardless of outcome, drives the problem forward along the path toward its solution.

Prelude

During the brainstorming stage, one teammate proposed hemorrhoids as our research focus. The idea immediately drew everyone's attention-this disease is widely recognized in China.

Although it is neither as deadly as cardiovascular disorders nor as difficult to treat as cancer, its prevalence is notorious. A popular saying goes, "Nine out of ten people suffer from hemorrhoids", and people are often warned not to sit for long periods to avoid developing the condition.

In reality, hemorrhoids not only cause pain, bleeding, and risk of infection but also exert a negative impact on mental health, significantly reducing quality of life.

Curious about the real scale, we looked closer. The saying "nine out of ten" may sound like a folksy exaggeration, but it is in fact a common misinterpretation with some solid numbers behind it. Epidemiological surveys give this saying a kernel of truth. A 1997 nationwide study reported that 59.1% of Chinese adults had anorectal diseases, with hemorrhoids accounting for nearly 90% of those cases-about 51.6% overall. A 2012 survey found a similar picture: half of adults were affected by anorectal diseases, and 98% of these involved hemorrhoids. Global data echo the trend, showing that over half of people experience hemorrhoids at some point in life.

Paradoxically, despite its high prevalence, hemorrhoids remain underexplored in research. Several factors contribute to this gap:

1. Stigma and embarrassment limit surveys and reliable data collection.
2. Wide differences in symptom severity and treatment responses complicate mechanistic studies.
3. More critically, research funding and investment tend to favor diseases with higher mortality or financial return, leaving hemorrhoids overlooked. Yet the socioeconomic burden is substantial- in the United States alone, annual costs are estimated at 800 million USD, largely due to hemorrhoidectomy procedures.

At the patient level, awareness and care-seeking behaviors are far from ideal. The 2012 Chinese survey found that only half of the diagnosed patients were even aware of their condition. Many avoided medical consultation due to negligence, privacy concerns, or social taboos.

Conservative treatments (ointments, sitz baths, dietary adjustments) often provide limited relief, while surgery entails painful and lengthy recovery. Without long-term lifestyle changes, recurrence remains common. These realities suggest that surgery is not an ideal long-term solution, and conventional medications show inconsistent efficacy. Current drug development efforts mainly focus on small molecules or herbal formulations, with little progress in biomacromolecular therapeutics.

Considering the trends in pharmaceutical research and the potential of synthetic biology, we believe there is a pressing need to design innovative, mechanism-based therapies for hemorrhoids. Such approaches could enable more precise, effective, and personalized treatment strategies.

Bridge

After selecting hemorrhoid treatment as our research focus, we conducted a comprehensive investigation into its pathological mechanisms to guide targeted intervention strategies.

The core pathology of hemorrhoids lies in vascular abnormalities within the anal cushions, leading to hemorrhoid formation and associated bleeding and pain. Studies show that vascular endothelial growth factor(VEGF) is significantly upregulated in hemorrhoidal tissue, promoting angiogenesis, vasodilation, and connective tissue degradation, which facilitates hemorrhoidal prolapse. Thus, targeting the hemorrhoidal tissue directly and inhibiting VEGF activity represents a key strategy for precision treatment.

Prolonged sitting or standing, irregular bowel habits, frequent constipation or diarrhea, and insufficient dietary fiber or water intake increase anal cushion pressure and impede venous return, triggering or exacerbating hemorrhoids. Promoting scientifically guided lifestyle interventions is crucial for prevention and management.

Chronic stress, anxiety, or emotional instability can affect gut function and vascular tone, increasing hemorrhoid risk. Conversely, hemorrhoid-related bleeding, pain, and discomfort can lead to anxiety, depression, or social withdrawal. Addressing patients' psychological experience supports a comprehensive intervention approach.

Based on these findings, our project aims to suppress pathological proliferation at the molecular level, provide anti-inflammatory interventions to alleviate patient discomfort, and promote healthy lifestyle habits and accurate disease awareness to reduce psychological burden. Through Human Practices efforts, these goals have been distilled into three core principles:

Precision Therapy, Medicine-Food Collaboration, and Patient-Centered Approach.

Principle Ⅰ. Precision Therapy

After defining our goal of developing therapeutics for hemorrhoids, we conducted a systematic background investigation and identified clear gaps in existing treatments: current options are largely limited to chemically synthesized drugs or traditional Chinese compound formulations, while biologic therapeutics specifically targeting hemorrhoids remain scarce. This gap provided a clear direction for our project.

Through an in-depth study of the molecular mechanisms underlying hemorrhoid formation and progression, we found that aberrant angiogenesis and activation of inflammatory pathways play key roles. Based on these insights, we developed a preliminary project design, specifying drug targets, mechanisms of action, and delivery strategies, thereby laying a solid foundation for subsequent experiments and functional validation.

To ensure that our design is not only scientifically feasible but also considers the interests of multiple stakeholders-including patients, industry partners, healthcare professionals, the general public, and regulatory authorities-we repeatedly examined and optimized the project's circuit design. By gathering feedback and requirements from these diverse stakeholders, we aimed to create a design that fosters a positive cycle between scientific innovation and societal value.

Cycle 1. Refining Degradation Strategy

When designing the HIF-1α degradation strategy, we initially considered using tag proteins to activate the Chaperone-Mediated Autophagy (CMA) pathway. However, preliminary analysis indicated that the degradation efficiency via this pathway might be limited, necessitating an adjustment to our degradation strategy.

Literature review indicates that under normoxic conditions, HIF-1α is primarily regulated through the ubiquitin-proteasome system (UPS), whereas under hypoxic conditions, autophagy pathways mainly maintain its homeostasis. However, due to the relatively low degradation efficiency of autophagy, HIF-1α tends to accumulate in the cell and translocate to the nucleus, where it activates hypoxia-responsive signaling pathways.

We invited Professor Xiaoyan Zhang, an expert in the field of autophagy, to discuss our design for HIF-1α degradation. During the exchange, we consulted her on common strategies and research approaches in autophagy, seeking insights to refine our project design.

Professor Zhang emphasized that both the ubiquitin-proteasome system (UPS) and autophagy are major protein degradation pathways in eukaryotic cells, playing essential roles in maintaining cellular homeostasis. She suggested several possible directions to optimize our HIF-1α processing strategy:

1. Enhancing the efficiency of the CMA pathway-for example, by overexpressing LAMP1 to reduce HIF-1α accumulation.
2. Exploring alternatives beyond intracellular degradation, such as promoting exosomal secretion of HIF-1α to lower its intracellular concentration.

Building on Professor Zhang's suggestions, we further evaluated the feasibility of the proposed strategies. Although enhancing CMA efficiency and promoting exosomal secretion were not applicable to our OMV-based delivery system, the discussion gave us a more comprehensive understanding of autophagy and provided valuable inspiration for our circuit design.

Ultimately, we decided to develop a bioPROTAC approach to achieve targeted degradation of HIF-1α through the ubiquitin-proteasome system (UPS).

Cycle 2. Defining Pharmaceutical Positioning

As the project progressed, we realized that relying solely on internal discussions and experimental design made it difficult to fully identify potential issues or avoid policy-related risks. Therefore, it was necessary to engage in broader communication with external authorities and experts to obtain professional insights and policy guidance, ensuring the compliance and feasibility of our project.

Through SWOT analysis, we identified potential weaknesses in policy and regulatory aspects of our project, particularly concerning drug approval, product safety, and market compliance. Therefore, we recognized the importance of proactively establishing communication channels with government and regulatory bodies to better understand policy requirements and obtain guidance for optimizing our project design.

To this end, we held discussions with Zhang Zhanduo, Deputy Director of the Binzhou Municipal Administration for Market Regulation; Hao Ziyi, Director of the Food Division; Sun Keke, Director of the Drug Division; Director Niu from the Food Safety Division; and Li Wenkai, Member of the Party Leadership Group of the Binzhou Municipal Health Commission and Senior Supervisor of the Discipline Inspection and Supervision Team stationed there.

During the meetings, we presented our project's research concept, technical framework, and envisioned applications in detail. The discussions focused on the project's feasibility within existing regulatory frameworks, including drug approval procedures, product safety standards, and potential legal compliance issues. Through these exchanges, we sought professional insights to further refine and optimize our project design.

Director Sun from the Drug Division explained that pharmaceutical products must have clearly defined active ingredients and therapeutic effects. To qualify as a drug, a product must meet six essential criteria: prevention, diagnosis, treatment, indications, dosage and administration, and defined active ingredients.

In contrast, health supplements fall under the category of special foods and may only claim to regulate physiological functions-any mention of therapeutic effects is strictly prohibited. Director Niu from the Food Safety Division emphasized that if a product claims to treat specific diseases such as hemorrhoids, it must be classified as a drug; otherwise, it would face regulatory non-compliance risks.

Li Wenkai, Head of the Discipline Inspection and Supervision Group at the Municipal Health Commission, noted that from a policy perspective, the state maintains a clear and supportive stance toward bioproduct development, though the approval process remains longer and subject to more rigorous standards.

Through this exchange, we ultimately determined to position our project as a pharmaceutical product.

This decision not only clarified our research and development direction but also prompted the team to further refine the safety module, ensuring controllability and traceability under pharmaceutical standards. This module later evolved into Principle Ⅱ. Medicine-Food Collaboration - symbolizing the fusion of scientific design and practical application, and laying a solid foundation for the project's further development.

Cycle 3. Clarifying Usage Approach

The CCiC (Conference of China iGEMer Community) is a highly influential communication platform that was first initiated by HZAU-China in 2014. Each year, we actively participate in this conference, presenting our project to peers in the synthetic biology community and reflecting together on its potential limitations and areas for improvement.

Unclear routes of administration (oral vs. topical):

Indeed, in our previous design, we merely proposed the possibility of both oral and topical applications without specifying their respective forms or mechanisms. Many teams suggested that we should further clarify the exact mode of administration.

Concerns about forced dietary intervention:

Some participants pointed out that requiring patients to strictly follow a prescribed diet could be burdensome and impractical. Meanwhile, Tongji-China inspired us with a contrasting perspective. Their project focused on meeting astronauts' specific dietary needs as a form of human-centered care. Although our two teams adopted completely different approaches, both shared the same human-oriented goal, prompting us to reflect deeply on the balance between scientific design and user experience.

After the conference, our team engaged in an intense and enduring discussion around these two key points of contradiction. We decided to confront these challenges directly rather than avoid or oversimplify them.

First, we clarified the routes of action for each therapeutic molecule. By analyzing the logical relationships among different drugs, we found that their effective sites vary. For example, bioPROTAC must enter the cell to bind and degrade HIF-1α; anti-VEGF functions extracellularly by binding to VEGF factors; and melittin, an anti-inflammatory peptide, also acts on the cell membrane surface.

Furthermore, we discovered that anti-angiogenic drugs may cause adverse effects in pregnant women-a finding that contradicted our Principle Ⅲ. Patient-Centered Approach, reinforced after our Mother's Day public engagement, that our therapy should remain suitable for pregnant patients. This prompted us to separate the anti-angiogenic and anti-inflammatory modules.

Ultimately, we decided to encapsulate HIF-1α bioPROTAC within OMVs for intracellular delivery, while keeping anti-VEGF as an extracellular molecule independent of OMVs. Together, these agents function as orally administered exosomal therapeutics to shrink hemorrhoidal tissue and achieve precise treatment. However, since anti-VEGF no longer relied on OMV membranes for targeting, it lost its inherent specificity. To address this issue, we adopted a Probody-based design, incorporating a linker cleavable by MMP3, which is highly expressed in hemorrhoidal lesions. This mechanism allows anti-VEGF to regain its activity specifically at the lesion site, enabling localized and targeted therapy.

For the topical formulation, melittin was designed to exert anti-inflammatory effects, particularly suited for pregnant patients and those requiring rapid relief from acute inflammation and pain. Its targeting specificity and safety are ensured through a four-layered mechanism:

1. Engineering optimization inspired by the NKU-China 2024 team;
2. The natural aggregation tendency of E. coli Nissle 1917 (EcN) at inflammation sites;
3. Quorum-sensing regulation that controls peptide expression;
4. An ROS-responsive promoter that activates only in inflamed microenvironments.

Regarding the discussion on "forced dietary intervention," we recognized it as a tension between our philosophy of dietary cooperation for enhanced therapeutic outcomes and the public's desire for a treatment that works without dietary restrictions.

To address this, we engaged in further conversations with patients, adhering to our Principle Ⅲ. Patient-Centered Approach. Through these exchanges and value-based reflections, we chose a balanced approach-broadening the range of compatible foods so that patients could have more freedom of choice.

Of course, through continued exploration, our Principle Ⅱ. Medicine-Food Collaboration was further refined to better accommodate diverse patient needs while preserving our original intent of integrating dietary modulation into therapy.

If you're interested in how this concept evolved, you can learn more in that section.

Cycle 4. Rethink Our Research Direction

To validate our design concepts and experimental direction, we sought professional guidance from experts in molecular biology. Our goal was to identify potential issues, refine our strategies, and obtain constructive feedback to support the project's advancement.

We invited Professor Zijian Tang for an in-depth discussion, where we presented our drug design targeting HIF-1α and VEGF, along with the delivery strategies and expected therapeutic outcomes. We also consulted him on how to proceed with experiments when the underlying molecular mechanisms remain only partially understood, and whether combined intervention approaches might offer a more reliable route.

Professor Tang expressed strong interest in our final experimental results and affirmed the creativity of our design. However, he also noted that from a biological research perspective, HIF-1α and VEGF belong to the same signaling pathway, and dual targeting within a single pathway is relatively uncommon. Researchers typically select key molecules from different pathways to achieve more pronounced synergistic effects.

Guided by this feedback, we reflected deeply on our strategy. Given that the molecular mechanisms underlying hemorrhoids remain incompletely characterized and the number of well-defined effector molecules is limited, we decided to focus our study on the VEGF signaling pathway.

Building upon this foundation, we elevated our project goal from developing two specific inhibitors to establishing a generalizable intervention framework:

• Intracellular inhibition via OMV + bioPROTAC, enabling precise control of intracellular pathways;
• Extracellular modulation through Probody and Nanobody designs, achieving region-specific activity.

This refined strategy preserves the project's innovative spirit. Instead of relying on a single molecular intervention model, we developed multiple approaches designed to adapt to diverse therapeutic needs in the future.

Cycle 5. Exploring Commercialization Feasibility

As our project progressed, we realized that pushing a therapeutic solution toward commercial application requires a clear assessment of its feasibility and development challenges. Therefore, we sought to communicate with industry experts to identify both the strengths and potential obstacles of our design in commercialization, helping us strike a balance between academic exploration and market practicality.

We focused on Mayinglong Pharmaceutical Group, a leading enterprise in the field of hemorrhoid treatment, to study its position, research pipeline, and development strategies. By analyzing its experience in drug development and commercialization, we aimed to draw insights for evaluating the feasibility and risks of applying bioPROTAC technology to real-world markets.

To deepen our understanding, we held an in-depth discussion with Dr. Liu Wei from Mayinglong. We introduced the core principles and expected therapeutic effects of our project, and sought her professional perspective on its potential for commercialization.

Dr. Liu acknowledged the novelty of our approach but sharply pointed out the potential challenges our project may face in commercialization.

1. Development Difficulty - PROTAC drug development involves a very high technical threshold. Traditional structure–activity optimization strategies are difficult to apply, and Mayinglong currently prioritizes drug development targeting well-validated molecules. This suggests that our approach may face considerable challenges in market readiness.
2. Lack of Evaluation Models - The project currently lacks essential evaluation systems such as cell- or animal-based models, making it difficult to assess the therapeutic efficacy and safety of our design.
3. Target Risk - The biological correlation between HIF-1α and hemorrhoid pathology remains unclear. There are no knockout models or disease association data to support this target, and no related drugs have yet entered clinical trials, indicating a high potential risk for this target.

Based on Dr. Liu's feedback, we made the following decisions:

1. Innovation Retained - As an iGEM project, we decided to continue exploring the development of HIF-1α bioPROTACs. Our goal is to validate the concept and demonstrate technological innovation rather than pursue immediate market application.
2. Experimental Strategy Adjustment - We initiated cell-based experiments to evaluate the molecular effects of our drug design in vitro. However, considering time, ethical, and resource constraints, we decided not to perform animal or organoid studies this year. Such investigations will be reserved as future development directions.
3. Reflection and Outlook - The discussion reaffirmed that the molecular mechanisms underlying hemorrhoids remain insufficiently studied-consistent with our earlier findings. This supports our decision to prioritize strategic exploration over clinical translation at this stage. We call for more researchers to focus on elucidating the molecular pathways of hemorrhoids, which will provide essential foundations for future drug discovery and rational target selection.

Throughout our Human Practices work, our project underwent multiple rounds of iteration and refinement, constantly evolving toward a design that is more scientific, feasible, and socially relevant.

Through discussions with Professor Zhang Xiaoyan, we optimized our degradation strategy, significantly enhancing the efficiency of HIF-1α degradation. Interactions with government and regulatory bodies helped us clarify our project's positioning and guided a series of safety and compliance improvements. Inspired by our synthetic biology peers, we redefined our application scenarios and initiated in-depth conversations with patients and clinicians, which directly reshaped our project direction.

Furthermore, exchanges with Professor Tang Zijian and experts from Mayinglong Pharmaceutical elevated our focus from developing a specific therapeutic molecule to exploring delivery strategies with broader applicability. This shift not only expanded the scope of our innovation but also provided a transferable framework for future biopharmaceutical design.

Through this journey, we call on the scientific community to pay more attention to hemorrhoids and other diseases that, while rarely fatal, profoundly affect quality of life. By integrating modern biological tools and patient-centered values, we hope our exploration will not only advance our project but also inspire future research on the molecular mechanisms and therapeutic strategies of such overlooked conditions.

Principle Ⅱ. Medicine-Food Collaboration

In the following section, we highlight our team's spark of inspiration, persistent exploration, and iterative refinement of the concept of Medicine–Food Collaboration. As a novel logic of living therapeutics that can only be realized through synthetic biology, this idea has drawn significant interest from our peers, which in turn strengthened our determination to push the concept further.

By linking dietary intervention with the safety module, we designed a system where food acts as the signal to regulate the colonization of engineered bacteria. During treatment, patients simply maintain a specific dietary structure to sustain continuous drug activation. Once the therapeutic cycle ends, discontinuing the intake of those specific foods for a few days will automatically and permanently deactivate the bacteria until the next administration begins.

This concept embodies the unique strengths of synthetic biology: programmability, controllability, and personalization. Through continuous iteration and refinement, our team gradually established a practical and adaptable framework for Medicine–Food Collaboration, eventually compiling it into a handbook that may serve as a valuable reference for future research and applications.

Cycle 1. Origin of the Medicine-Food Collaboration

At the early stage of our project, we communicated with relevant government departments to clarify the regulatory and positioning requirements for our therapeutic design. This dialogue helped us define the project's scope more precisely while also introducing new safety considerations: the engineered bacteria must not persistently colonize the human gut, and there must be a reliable mechanism to terminate drug delivery after the treatment period ends.

However, we soon realized that the self-killing system designed in our early stage was not fully compatible with the current therapeutic scenario. As a therapeutic agent, the design of a safety module is of paramount importance. Our safety module functions as both a switch to halt drug delivery and a barrier to prevent accidental leakage. However, in the human intestinal environment, we cannot rely on external inducers such as TPP for regulation. Therefore, we needed to identify a more suitable control mechanism.

During the brainstorming stage, we discovered that lifestyle modification plays a crucial role in hemorrhoid intervention. This insight reminded us of our original intention-to explore solutions that go beyond drugs and address the problem through daily habits. We realized that if we could integrate lifestyle factors into the safety regulation of our therapy, it would create a more holistic and sustainable design.

Literature review confirmed that dietary intervention indeed plays a non-negligible role in the treatment and management of hemorrhoids. Both modern medicine and traditional Chinese medicine regard diet as an essential adjunct therapy-not only capable of alleviating symptoms by improving gut function but also of supporting overall physiological balance to facilitate recovery.

Motivated by these findings, we began exploring the integration of medicine and food, enabling dietary cues to modulate therapeutic activity.

We call this innovative approach "Medicine–Food Collaboration."

During the practical phase of our project, we interviewed several chief physicians and associate chief physicians working on the clinical front line. Through these in-depth conversations, we sought to draw on their extensive clinical experience to better understand patients' dietary habits and the degree of emphasis placed on dietary regulation within current treatment protocols. Insights from these medical professionals not only validated the real-world relevance of our Medicine–Food Collaboration concept but also provided valuable guidance for refining our system design.

Xu Yuejun, Chief Physician of the Department of Colorectal Surgery, Wuhan Eighth Hospital, noted that coarse-fiber foods effectively promote intestinal peristalsis and relieve constipation, thereby reducing hemorrhoid-related symptoms. In addition to standard medical treatment, doctors often recommend that patients adopt dietary interventions-such as increasing fiber intake and maintaining a light, balanced diet. These lifestyle-level adjustments have shown promising results in improving patients' overall health, particularly in long-term management and recurrence prevention, which supports the validity of our concept of treating diseases through dietary regulation.

At Wuhan No. 8 Hospital, a specialized patient cafeteria has even been established to provide scientifically managed meals that improve intestinal health and dietary habits, helping prevent the recurrence of anorectal diseases such as hemorrhoids. This well-structured platform for dietary intervention demonstrates that an organized dietary management system can, to some extent, serve as a practical foundation for implementing the Medicine–Food Collaboration concept.

We found that dietary intervention is not only a promising direction identified through our investigation, but also a scientifically validated and widely recommended approach in clinical practice. Frequently emphasized by physicians and commonly adopted by patients, it effectively alleviates symptoms, promotes recovery, and helps prevent the onset and recurrence of hemorrhoids by improving lifestyle habits.

In this process, food transcended its conventional role as a mere therapeutic aid and became a bridge linking clinical wisdom, public habits, and synthetic design. From physicians’ recommendations to patients’ daily practices, we realized that dietary regulation represents not just a lifestyle adjustment but a deeply embedded therapeutic rationale in hemorrhoid management.

Cycle 2. Selecting Suitable Food Materials

After establishing the concept of Medicine–Food Collaboration, our next step was to identify a representative food to be integrated into the project design. After extensive discussion, we determined that our target food must meet the following criteria:

1. It should possess well-documented health benefits, such as promoting intestinal motility to prevent constipation, improving blood circulation, or alleviating hemorrhoid symptoms.
2. It should contain distinct small-molecule compounds capable of interacting with known riboswitch aptamers, thereby serving as an effective signal for the sensing elements in our regulatory circuit.
3. It should be compatible with patients' dietary habits, ensuring the sustainability and practicality of dietary intervention.

Therefore, the selection of a suitable food required comprehensive consideration of its clinical efficacy, molecular mechanism, and patient acceptance.

In our preliminary investigation, physicians repeatedly emphasized the crucial role of dietary fiber in managing hemorrhoid-related conditions, which prompted us to conduct an in-depth study on this topic. We found that whole grains, legumes, vegetables, and fruits-all components of a healthy diet-are naturally rich in coarse dietary fiber. These foods, when combined into a Mediterranean-style dietary pattern, also provide strong antioxidant and anti-inflammatory benefits, making them an excellent choice for promoting intestinal health.

At the same time, China has been actively promoting whole-grain consumption. The National Whole-Grain Action Plan, launched in 2024, encourages increased intake of whole grains and highlights the health benefits of dietary fiber. This national initiative aligns perfectly with the goals of our project, reinforcing the relevance and societal value of our design.

To our delight, Huazhong Agricultural University has actively responded to the national Whole-Grain Action Plan, hosting multiple science outreach events this year. Members of HZAU-China seized this opportunity to participate as volunteers, contributing to public education on whole grains, the Mediterranean diet, and other healthy eating habits-all of which can effectively help prevent hemorrhoid-related diseases.

Meanwhile, these outreach activities became a process of mutual learning. By engaging with experts and the public, our team gained deeper insights into whole-grain nutrition and its physiological benefits, which in turn informed our selection of appropriate food candidates for the development of our Medicine–Food Collaboration framework.

During our science outreach activities, we were inspired to take a closer look at black rice, a traditional whole grain widely consumed in East Asia. We found that it is exceptionally rich in dietary fiber and anthocyanins two components that have long been associated with intestinal health and disease prevention.

Dietary fiber has been proven to enhance gut motility, promote bowel regularity, and thereby reduce hemorrhoid symptoms triggered by constipation. Meanwhile, anthocyanins exert anti-inflammatory and antioxidant effects, helping to protect the intestinal mucosa, alleviate oxidative stress, and support vascular health. These combined properties make black rice an ideal candidate for our Medicine–Food Collaboration framework-one that not only aligns with common dietary preferences but also offers scientifically validated physiological benefits that can be integrated into our biological design.

Anthocyanins, naturally occurring bioactive molecules abundant in black rice, blueberries, and legumes, are key nutritional components of the Mediterranean diet-a dietary structure widely recognized for its anti-inflammatory and antioxidant benefits. We envisioned leveraging this diet as a regulatory framework, allowing our riboswitch system to specifically respond to anthocyanin molecules as dietary signals.

Among these foods, we selected black rice as the representative and symbolic case for integration into our project design. As a staple food that is both scientifically validated and culturally familiar, black rice bridges the gap between daily nutrition and synthetic biology regulation. Through this choice, we sought to demonstrate how a simple, accessible food can serve as a precise molecular cue within a living therapeutic system-realizing the true potential of Medicine–Food Collaboration.

Cycle 3. Identifying Bioactive Small Molecules

We aimed to examine whether the selection of black rice and anthocyanins was scientifically and practically justified. To achieve this, we conducted a comprehensive investigation from multiple perspectives, including Human Practices and modeling, integrating qualitative insights with quantitative analysis to ensure the robustness of our design.

We found that no mature aptamer for anthocyanins has been developed so far, which poses a practical limitation for riboswitch construction. Meanwhile, pharmacokinetic simulations conducted by our Dry Lab revealed that anthocyanins are metabolized rapidly in vivo-typically within just a few hours-making it difficult to sustain riboswitch activation.

Interestingly, our analysis identified hippuric acid, a major metabolic product of anthocyanins, as a promising alternative. It exhibits favorable pharmacokinetic properties, including a longer half-life and greater stability in the body, suggesting its potential as a more suitable ligand for our system.

We had the honor of interviewing Professor Mei Zhinan from Huazhong Agricultural University, a leading scholar whose research bridges Traditional Chinese Medicine (TCM) modernization, medicinal plant genomics, and synthetic biology. As an independent board member of the Mayinglong Pharmaceutical Group, Professor Mei also brings a wealth of clinical and industrial insights into hemorrhoid treatment.

During the interview, we discussed the current state and future potential of TCM in hemorrhoid therapy, with a special focus on our project's concept of Medicine-Food Collaboration. Professor Mei emphasized the unique advantages of TCM, particularly its ability to regulate intestinal function and alleviate inflammation. He noted that traditional herbs such as Sophora flower and Radix Sophorae flavescentis have shown therapeutic effects in relieving pain and swelling, though their efficacy tends to emerge gradually rather than immediately, contrasting with the rapid action of modern pharmaceuticals.

Professor Mei also highlighted the TCM principle of "treatment based on syndrome differentiation," which emphasizes individualized care. He expressed strong interest in our Medicine-Food Collaboration framework, recognizing it as an innovative integration of modern biotechnology and traditional therapeutic wisdom. This approach, he suggested, could achieve precise and side-effect-free therapeutic control, offering new possibilities for the modernization of TCM.

Moreover, he reminded us that food selection and pairing should be pharmacologically informed, not merely auxiliary, to maximize synergistic efficacy. Building on his insights, we further explored how engineered microbial regulation could interact with food metabolites to enhance treatment outcomes. Professor Mei's valuable guidance provided both conceptual depth and practical direction for the development of our Medicine-Food Collaboration strategy.

During our discussion with Professor Mei, he pointed out that although anthocyanins and similar compounds exhibit strong bioactivity, their rapid metabolism in the gut may make them unsuitable for long-term or sustained therapeutic applications. Therefore, when selecting food-derived molecules for our system, it is important not only to consider their therapeutic efficacy but also to account for intestinal metabolism, favoring components that are metabolized more slowly and retain activity for extended periods.

However, choosing hippuric acid, the metabolic product of anthocyanins, presents another challenge. Hippuric acid is produced by the metabolism of various foods, which limits its specificity. If our riboswitch system requires a specific dietary signal, the presence of hippuric acid from other foods could interfere with the intended regulatory link, compromising the precision of the Medicine–Food Collaboration framework.

With this feedback, we encountered a significant dilemma. Initially, we considered black rice to be an ideal food closely aligned with our project. However, during the design process, we encountered a critical bottleneck: even among seemingly suitable foods, it was difficult to identify compatible small-molecule signals for the riboswitch.

This left us with a challenging decision. One option was to abandon black rice and select an alternative food. The other was to retain black rice, but make a trade-off between the specificity of anthocyanins and the metabolic stability of hippuric acid. Each path presented distinct advantages and limitations, forcing us to carefully weigh practical feasibility against conceptual alignment with our Medicine–Food Collaboration framework.

Cycle 4. Confronting Conflicts in Principles

With these questions in mind, we attended the Conference of China iGEMer Community (CCiC). There, we engaged in exchange and discussion with other teams, sharing our ideas and learning from their experiences. During these interactions, we also faced constructive skepticism regarding our concept, which challenged us to re-evaluate and refine our approach to Medicine–Food Collaboration.

Some peers raised the concern that mandating patients to consume a specific "healthy" food could provoke resistance or even negatively affect their quality of life, since dietary habits are themselves an important aspect of daily living. Our project, after all, is grounded in addressing hemorrhoids-a condition that already compromises quality of life-and our goal has always been to provide a solution that is as comfortable as possible for patients.

For instance, during the conference, we observed that Tongji-China team exemplified their human-centered approach by adapting their interventions to patients' existing dietary habits. This prompted us to critically reflect on the feasibility and practicality of our own concept, and consider how best to balance therapeutic efficacy with patient comfort.

Our Medicine–Food Collaboration concept soon encountered a second major dilemma. Specifically, the idea of using dietary interventions as part of the treatment conflicted with our principle of human-centered care and patient comfort. We realized that we needed to carefully balance these two priorities, finding a compromise that would allow us to maintain both therapeutic effectiveness and respect for patients' autonomy and lifestyle.

Cycle 5. Engaging with Patients to Resolve Contradictions

When we first proposed the Medicine–Food Collaboration concept and selected black rice and the Mediterranean diet as representative cases, we were full of confidence in this creative approach. However, during subsequent exploration, we identified two major dilemmas:

1. Mandating patients to consume specific foods could compromise their quality of life, conflicting with our principle of patient-centered care.
2. In selecting suitable foods, we realized that it is extremely challenging to find small molecules that are both specific and metabolically stable, limiting their practicality as regulatory signals.

To better resolve the contradictions we encountered during our research, we adhered to a patient-centered philosophy. We engaged deeply with patients in online support communities, listening to their experiences and concerns. Through multiple rounds of dialogue, we discussed our current "Medicine–Food Collaboration" concept with them, seeking to bridge the gap between scientific design and real-world needs. These conversations not only helped us reconcile theoretical and practical conflicts, but also made our design more empathetic, relevant, and grounded in genuine patient perspectives.

We began our interviews by exploring patients’ understanding of dietary interventions. As anticipated, most participants demonstrated a clear awareness of the vital role diet plays in both the prevention and management of hemorrhoids, often drawing from their own daily experiences.

Nevertheless, a few patients expressed uncertainty or limited knowledge in this regard, revealing that the significance of dietary regulation is not yet fully recognized by everyone.

Interestingly, some patients acknowledged that they were fully aware of the consequences of poor dietary habits, yet they still chose to maintain their existing eating patterns after weighing the pros and cons. This group exemplifies the very contradiction we previously discussed - the tension between health awareness and behavioral persistence.

Next, we introduced the concept of Medicine–Food Collaboration from our project and engaged patients in open discussion. Two distinct perspectives emerged: most participants found the design intriguing and expressed willingness to try such an approach, emphasizing that it seemed both natural and safe to them.

However, some participants voiced reservations. A few believed that existing treatment methods were already effective and questioned whether our approach could offer additional benefits. Others were skeptical about the involvement of food itself, expressing a preference for simpler or more effortless treatment options that would not necessarily rely on dietary regulation.

The patient feedback revealed diverse needs and specific concerns regarding dietary interventions during treatment. Through these discussions, we learned that many patients do not prioritize rapid cure above all else; they value comfort and flexibility throughout the therapeutic process. Moreover, many patients do not follow a traditional three-meals-a-day routine, making it difficult to increase meal frequency. This posed a problem: using rapidly metabolized molecules such as anthocyanins would require patients to consume the same food multiple times per day, which could be burdensome.

In response to these findings, we iterated our Medicine–Food Collaboration concept to find a balance between these conflicting requirements.

1. Although it was a difficult decision, we decided to remove black rice from the project, as neither anthocyanins nor hippuric acid could meet the requirements identified through our investigations.
2. We adjusted our original dietary plan to adopt a more flexible and personalized intervention model, termed the "N+1" framework. This means that we tried to explore a wider range of foods and dietary patterns to accommodate patients with different preferences; in special cases, we could also design an additional candy formulation containing the corresponding bioactive molecules, allowing patients to maintain therapeutic effects without strictly adhering to a specific diet.

Integration Details

To address the aforementioned contradiction, we have dedicated efforts to identifying novel small molecules:

As mentioned, we require a group of specific small molecules that are abundantly present in healthy foods and can remain in the intestinal tract for as long as possible. Inspired by mannitol—a classic small molecule widely used in medicine known for its prolonged retention in the intestines—we established a series of qualitative screening criteria, including resistance to digestion and absorption, and inability to be synthesized by gut microbiota. Based on our preliminary literature review, we conducted an initial screening.

This figure illustrates a range of physicochemical properties of mannitol predicted using the ADMETlab website, including its Absorption, Distribution, Metabolism, Excretion, and Toxicity. This platform played a crucial role in our early-stage screening of small molecules, aiding in the prediction of various properties of candidate compounds.

Properties of Gastrointestinal-Retentive Small Molecules

This figure presents the results of our literature review, showcasing the six primary indicators considered in the first phase. Clockwise, these are: Human Intestinal Absorption (HIA), Molecular Weight (MW), Topological Polar Surface Area (TPSA), Lipid-water Partition Coefficient (LogP), Caco-2 Permeability, and Bioavailability (F20%).

As clearly depicted, the desired properties of gastrointestinal-retentive small molecules are largely contrary to those required for highly absorbable small molecules in drug design and prediction. The most intuitive reason is that the core requirement for drug molecules is their ability to be absorbed by intestinal epithelial cells and enter the circulatory system to reach target sites for therapeutic effects. In contrast, our project requires small molecules to remain in the intestinal lumen for an extended period while avoiding absorption by the human body—properties that are fundamentally opposite to those of drug molecules. Consequently, throughout the screening process, we found it challenging to identify directly applicable references, both in the literature and in existing models.This led us to achieve some preliminary outcomes in the first phase, albeit with great difficulty.

This figure displays some of our initial outcomes, specifically molecules that performed well under our evaluation system. However, due to limitations in our screening framework and a lack of relevant data, some unsuitable molecules remained mixed in. Punicalin, shown in the fourth row of the table, is a notable example. While it met many of our physicochemical requirements, issues arose regarding its distribution. It is abundant in pomegranate peel but constitutes only a minor component in pomegranate pulp, making it impractical to develop recipes associated with it.

Despite the scarcity of data, we were not satisfied with the existing approach of qualitative description and manual screening. Thus, we proposed a new solution. We identified the Human Metabolome Database, where the fecal small molecule database particularly caught our attention. Some of these small molecules must have met our criteria to pass through the entire digestive tract and eventually be excreted in feces. These molecules undoubtedly possess relevant properties.

After further extensive literature review, we decided to employ the one-class SVM method for independent quantitative analysis to enhance the reliability and systematization of our screening. One-class SVM is an unsupervised machine learning approach that constructs a decision boundary in the feature space by analyzing known positive samples, enabling the rapid identification of new samples highly similar to the established pattern. Using SVM, we could classify these small molecules based on various indicators within the dataset, thereby further identifying the key physicochemical properties influencing intestinal retention time.

his figure summarizes the results of our SVM-based data analysis, ranking the various physicochemical indicators of small molecules according to their influence on intestinal retention time. The top five indicators identified were: refractivity, rotatable bond count, mono mass, polarizability, and LogP. Subsequent literature verification confirmed these five indicators as key factors in small molecule screening, representing a significant milestone in our work.

However, certain issues remain. Since these indicators may interact or even exhibit inclusion relationships under certain circumstances, our SVM results were somewhat affected. For example, among the top five indicators, refractivity and polarizability reflect highly similar molecular properties and show a significant negative correlation with LogP. Mono mass indirectly influences most of the indicators in this bar chart, among other issues. These observations not only demonstrate the sensitivity and complexity of our model but also highlight that the physicochemical properties of small molecules are determined by numerous interrelated indicators. Our work provides a preliminary exploration of this screening process, and further analyses such as Principal Component Analysis (PCA) may be required for deeper insights.

Despite these challenges, we have endeavored to outline a complete research pathway from qualitative initial screening to quantitative mining. We have not only clarified the fundamental opposition between gastrointestinal-retentive small molecules and traditional drug molecules in terms of physicochemical properties but also leveraged machine learning models to precisely identify the five most influential core indicators from vast datasets.

The significance of this work lies in its provision of a critical molecular feature network and quantifiable screening criteria for our subsequent engineering of bacterial designs. Although the current model suffers from entangled and interdependent indicators, this precisely reveals the complexity of biomolecular interactions and directs our next research steps: employing dimensionality reduction techniques such as PCA to reconstruct the feature space, isolate confounding factors, and build a purer, more efficient predictive model. Ultimately, this will lay a computational foundation for achieving precise personalized "Medicine-Food Collaboration".

Under this model, we ensure therapeutic efficacy while providing patients with greater dietary choice, thereby reconciling treatment precision with patient comfort and autonomy.

Cycle 6. Attempting to Expand with Nucleic Acid Aptamers

As we began to expand the variety of foods in our project, we encountered a critical limitation: the currently known repertoire of riboswitch aptamers is relatively narrow. This restricts the optimization and diversification of treatment strategies. Without a sufficiently rich library of aptamers, it becomes difficult to precisely sense and regulate multiple metabolic products, thereby limiting the feasibility of personalized therapy.

Consequently, expanding the diversity of riboswitch aptamers to cover a wider range of food-derived molecules has emerged as a core challenge for our upcoming research.

To address the bottleneck of limited aptamer diversity, we first considered using SELEX (Systematic Evolution of Ligands by Exponential Enrichment) to screen for new aptamers. SELEX is a high-throughput selection technique that progressively enriches nucleic acid molecules with high affinity and specificity for a target compound from a vast molecular library.

By applying this method, we can theoretically establish a larger and more precise riboswitch aptamer library, providing dedicated sensing modules for different food-derived metabolites. This, in turn, would enable more personalized and precise therapeutic interventions for patients.

Dr. Wang Xun, an expert in synthetic biology and systems bioengineering, has extensive experience in the selection and application of nucleic acid aptamers. We had an in-depth discussion with Dr. Wang regarding our plan to expand the library of aptamers using the SELEX technique, exploring the feasibility and potential challenges of this approach. The conversation provided us with valuable insights into experimental design and selection strategies, helping us refine the technical roadmap for our future work.

Dr. Wang confirmed that screening riboswitch aptamers via SELEX is theoretically feasible and provided a detailed explanation of the experimental workflow and expected timeline. However, she also cautioned that the process comes with practical challenges, including high cost, lengthy duration, and uncertain success rates.

She highlighted several critical hurdles: after aptamer selection, it remains challenging to efficiently integrate them with synthetic biology expression platforms, and bridging the gap between in vitro validation and in vivo application requires extensive iterative experimentation. Additionally, Dr. Wang emphasized that although SELEX is relatively mature, the integration of computational modeling with experimental approaches still demands cross-disciplinary collaboration and iterative optimization.

After carefully considering time, cost, and project objectives, we decided not to conduct large-scale wet-lab SELEX experiments this year. Since our goal is to expand the diversity of aptamers to cover more food-derived molecules, we shifted our strategy toward computational modeling.

Specifically, we plan to develop an Aptamer de novo Design Model to predict and design nucleic acid aptamers corresponding to target small molecules. This approach not only enhances screening efficiency but also has the potential to lay the foundation for a systematic and scalable riboswitch aptamer database, providing robust support for precise and personalized hemorrhoid therapy in the future.

Cycle 7. Consulting Experts for Further Insights

We aimed to present our Medicine–Food Collaboration design to domain experts in order to anticipate potential flaws and gather professional feedback.

This process allows us to identify possible limitations in experimental implementation, patient adaptability, and therapeutic efficacy in advance, enabling strategic adjustments to optimize both feasibility and scientific rigor.

Dr. Zhenxia Chen, an expert in precision nutrition, provided valuable insights. In our discussions, we explored the possibility of integrating personalized nutrition concepts with Medicine–Food Collaboration. Building on this idea, we proposed a conceptual chain: personalized nutrition → personalized Medicine–Food Collaboration → personalized therapy. This framework not only strengthens the scientific foundation of our approach but also offers guidance for developing more precise and individualized treatment strategies.

Currently, our expanded design essentially seeks a balance between small molecule specificity and sustained efficacy, yet the number of practically applicable foods remains limited, meaning this compromise does not fundamentally resolve the core challenge.

Dr. Chen further reminded us of a frequently overlooked issue: whether food-derived small molecules can efficiently enter bacterial cells. If the molecules cannot cross the cellular barrier, the riboswitch will fail to sense them, rendering the entire design nonfunctional.

As a valuable suggestion, she recommended the metabolite 3-HPPA (3-hydroxyphenylpropionic acid), a breakdown product of anthocyanins. This compound not only retains a longer half-life in vivo but also readily penetrates bacterial cells, making it a promising candidate for implementation in the Medicine–Food Collaboration design.

Professor Zhenxia Chen not only highlighted the challenges we faced but also gave us confidence to refine our approach. We decided to re-examine the Medicine–Food Collaboration concept from a synthetic biology perspective.

Fortunately, our team realized that if the signal from food-derived small molecules could be converted into a persistent "internal signal" inside bacterial cells, we would no longer be constrained by the in vivo retention time of the molecules. This insight led to the design of a "expiry-date circuit", which allows the transient external signal of a small molecule to be transformed and maintained over time, fundamentally overcoming the limitations imposed by small molecule pharmacokinetics.

With this iteration, the Medicine–Food Collaboration circuit achieved a major advancement. We are no longer strictly dependent on a limited set of molecules with ideal pharmacokinetic properties, which greatly expands the range of usable foods and enables the integration of diverse dietary structures. This means that we have significantly broadened the spectrum of foods available for selection.

At the same time, we chose to retain black rice and whole-grain Mediterranean-style diets as a representative application scenario. This choice not only symbolizes the fusion of traditional dietary wisdom with modern biology, but also maintains practical relevance in our improved design, making it a key component of the Medicine–Food Collaboration concept.

From the initially simple "suicide" circuit, our design underwent multiple iterations and eventually evolved into the current Medicine–Food Collaboration concept, allowing patients to easily regulate our drug delivery system simply by adjusting their dietary patterns. To support outreach and education, we developed an AI-powered recipe assistant and compiled our experiences into a Medicine–Food Collaboration manual, providing a foundation for other teams to build upon and improve.

We recognize that Medicine–Food Collaboration, as a novel synthetic biology-based drug delivery strategy, has only begun to reveal its potential. We are confident that, as predictive models for nucleic acid aptamers improve and the riboswitch library expands, patients will eventually be able to input personalized dietary plans and generate corresponding Medicine–Food Collaboration platforms. Through this work, we hope to pave the way, inspire, and motivate fellow synthetic biologists, while welcoming feedback and suggestions from the broader community.

Principle Ⅲ. Patient-Centered Approach

As indicated by our preliminary research, hemorrhoids are closely influenced by psychological and mental factors. Recent studies suggest that anxiety, depression, and chronic mental stress can exacerbate both the symptoms and the discomfort experienced by patients, highlighting the need to consider patients' psychological state and overall quality of life, in addition to addressing the physiological lesions themselves.

At the same time, the WHO and the United Nations have repeatedly emphasized the importance of human-centered care and patient engagement under frameworks such as "people-centered health services" and "the right to health." With the ongoing implementation of China's "Healthy China 2030" strategy, public awareness and expectations regarding health are evolving, driving a shift from a disease-centered to a people-centered healthcare model.

Many iGEM teams have demonstrated similar value-oriented approaches. For instance, the St_Andrews team in their 2020 Shinescreen project incorporated public concerns and environmental considerations into the project through in-depth interviews, prioritizing user and societal value. Likewise, the TU Delft team in 2017 proactively engaged with farm users while developing a mastitis diagnostic tool, ensuring the product's practical adoption by the target population. These examples inspired us to recognize that scientific research is not merely a technical endeavor, but a practice oriented toward human needs.

All of these factors guided us toward a clear path: we established a people-centered vision and emphasized the value of humanistic care. This guiding principle is not static. Following government consultations, we clarified our product positioning as a therapeutic intervention, and to make our vision more concrete and aligned with real-world needs, we focused specifically on hemorrhoid patients, refining "people-centered" into "patient-centered."

This transformation means that every aspect of our project-from product design and development strategies to the user experience-is centered around the physiological, psychological, and social needs of patients, ensuring that our scientific outcomes truly enhance patient quality of life while aligning with international health initiatives and the responsibility-driven, care-oriented spirit advocated by iGEM.

Cycle 1. Focusing on Maternal Health

At the early stage of our project, team members raised a critical question: Why has a condition as common and impactful on daily life as hemorrhoids not seen more effective treatment options? Is it that patients do not seek new therapies and are content with the status quo? Or is it that, compared to high-mortality diseases such as cancer, hemorrhoids have received comparatively little attention from both academia and society, resulting in limited progress and innovation in therapeutic approaches?

This reflection highlighted a gap between clinical need and research focus, motivating us to investigate both the medical and social factors that have contributed to the persistent underdevelopment of hemorrhoid treatments.

In our preliminary research, we found that hemorrhoids are an extremely common yet long-neglected disease. Despite their high prevalence worldwide, the condition is often regarded as an "embarrassing" or "trivial" problem due to its private nature. As a result, many patients tend to rely on home remedies or over-the-counter treatments rather than seeking professional medical help-often delaying treatment until the disease significantly affects their quality of life.

This tendency toward delayed medical consultation arises not only from the stigma and sensitivity surrounding the disease but also from a historical lack of attention in medical research, which has traditionally focused on life-threatening conditions such as cancer. Consequently, hemorrhoids have been underrepresented in epidemiological studies and public health policies, leading to a persistent underestimation of their true burden and their impact on patients’ well-being.

However, with changes in population structure and lifestyle, people are paying greater attention to their quality of life. Meanwhile, the rise of social media and self-media platforms has made it easier for once-taboo health topics to enter public discussion. As a result, hemorrhoids-though long regarded as a private or minor condition-have gradually attracted increased attention from clinicians and public health researchers, owing to their high prevalence and significant impact on daily well-being.

Recent attention in obstetrics and public health highlights the disease burden during pregnancy, especially conditions affecting maternal comfort. Pregnancy-related hemorrhoids, a high-risk and often overlooked condition, have thus gained research focus. Physiologically, uterine expansion increases pressure on the inferior vena cava, while elevated progesterone relaxes vascular walls, promoting venous dilation and congestion. Constipation further elevates anorectal venous pressure. Together, these factors sharply increase hemorrhoid risk, particularly in the second and third trimesters, with nearly half of pregnant women affected. Limited safe treatment options leave many enduring physical discomfort and psychological stress. Addressing mental well-being is therefore crucial, as pregnant women are more susceptible to anxiety and depression.

Based on our preliminary findings, we discovered that pregnant women are more prone to hemorrhoids due to uterine expansion compressing venous return, while the incidence of psychological stress during pregnancy is also notably high. However, most existing treatments are unsuitable for use during pregnancy, leaving these women facing both physical pain and emotional distress.

To address this issue, HZAU-China team organized a Mother's Day special event that combined scientific outreach with humanistic care, aiming to raise awareness of maternal physical and mental health and ensure that mothers' pain would no longer be silently endured.

During the event, we distributed probiotic drinks to promote gut health, and used interactive games such as spin-the-wheel quizzes and Pictionary to make hemorrhoid education engaging and accessible. Participants also received "Seed Cards", on which children could write blessings for their mothers - symbolizing the shared growth of health and love.

The event received an enthusiastic response. We collected 192 questionnaires, gaining valuable insights into public perceptions and needs regarding hemorrhoid treatment. These data provided a solid foundation for the subsequent design and optimization of our project, and many participants expressed high expectations for our work.

In the early stages of our project, our understanding of hemorrhoids was largely limited to their social stigma and the tendency for people to avoid discussing them. However, analysis of questionnaires collected during our Mother's Day outreach activity revealed a more nuanced social perspective. Most respondents considered hemorrhoids embarrassing and would not voluntarily discuss the condition with others; even among younger and middle-aged groups, there was a strong sensitivity to privacy. At the same time, a significant portion of respondents believed that patients should not feel ashamed and demonstrated an awareness of the psychological burden associated with the condition.

This coexistence of avoidance and empathy highlights a dual societal lens on hemorrhoids: on one hand, there is avoidance and humor; on the other, understanding and care. These results may also reflect our sampling approach-questionnaires were distributed via campus booths and in-person visits, targeting a generally well-educated population, and those willing to participate might already exhibit higher levels of empathy.

Further cross-analysis revealed an interesting pattern: healthy individuals tend to experience more shame about hemorrhoids than patients themselves (with the exception of individuals who declined to disclose their own hemorrhoid history, who reported the highest shame). This suggests that in the context of hemorrhoids, "external stigma" imposed by society outweighs "self-stigma." Consequently, social labeling not only amplifies psychological pressure on patients but also discourages them from seeking medical attention or support.

Analysis of our questionnaire data revealed that social stigma surrounding hemorrhoids is more complex than we had anticipated, directly affecting patients' psychological burden and healthcare-seeking behavior. This prompted us to reflect: truly putting patients first requires not only addressing the disease itself but also responding to the broader social and psychological environment that patients navigate.

Based on this insight, we decided to focus on pregnant women as a key target population in our research and development. This commitment guided our design decisions, ensuring that the therapeutics we develop are safe and suitable for use during pregnancy. This principle guided us, under Principle I: Precision Therapy, to distinguish between oral and topical formulations and to develop multiple types of drug delivery forms tailored to different therapeutic needs.

This practice fully embodies the project's integrative approach: public feedback not only uncovers challenges but also directly shapes the priorities of our research and the forms of our human-centered interventions. Moving forward, we will continue to maintain this bidirectional engagement, fostering a virtuous cycle between scientific design and societal needs.

Cycle 2. Deepening Communication with Patients

As the project entered a new iteration, we revisited the 192 questionnaires collected during our previous round of investigation - and soon identified important limitations. Although the data provided preliminary insights into the stigma surrounding hemorrhoids, the scope and depth of the survey were insufficient.

First, the respondent group was too homogeneous. Our survey mainly targeted the general public, lacking direct engagement with patients and medical professionals, which limited its clinical and practical relevance.

Second, the questionnaire format constrained depth. Most questions focused on public perception and basic knowledge, rather than exploring patients' real treatment experiences, emotional burden, or doctors' clinical observations.

This reflection led us to realize that a single survey cannot capture the medical and social complexity of hemorrhoids. To address this gap, we decided to expand our research to include in-depth interviews and multi-stakeholder dialogues, seeking a more comprehensive understanding of the issue.

To broaden the scope and deepen the focus of our research, we conducted a systematic literature review and integrated the insights gained into the next stage of our project practices.

From the clinicians' perspective, we learned from qualitative analyses that in-depth interviews can effectively reveal how doctors make therapeutic decisions and how these decisions relate to patients' clinical symptoms and living conditions. These findings provided guidance for our subsequent communication with doctors, helping us focus on the reasoning behind treatment choices and the practical challenges in clinical practice.

From the patients' perspective, we found that many studies emphasize the importance of understanding patients' daily experiences and psychological feelings. This inspired us to refine our interview design-shifting attention from purely clinical indicators to patients' subjective experiences and overall quality of life.

Building on our preliminary survey, we aimed to gain a comprehensive understanding of both the medical and social dimensions of hemorrhoids. To this end, we conducted semi-structured interviews with clinicians and patients to explore clinical treatment strategies, patient experiences, and the impact of societal perceptions on disease management.

We interviewed Dr. Xu yuejun, Chief of Ward 2 at the Anorectal Disease Diagnosis and Treatment Center of Wuhan Eighth Hospital, discussing common treatment approaches at different disease stages and drawing on his clinical experience. Additionally, we sought Dr. Xu's insights on our project design to refine our therapeutic strategies, ensuring they are closely aligned with patient needs and clinical realities.

After CCiC, we engaged with online support communities for hemorrhoid patients and invited participants for in-depth interviews. A total of eight patients took part, sharing their experiences with the condition, treatment processes, and the impact of hemorrhoids on their daily lives. The insights gathered from these patients provided valuable reference points, allowing us to design treatment strategies that are more closely aligned with patients' real-world needs and daily routines.

During our interviews with clinicians and patients, we specifically gathered information on the commonly used topical drug forms in clinical practice, as well as patients' preferred types of topical treatments. This provided a practical basis for expanding the topical formulations under Principle I: Precision Therapy. At the same time, we solicited feedback from both doctors and patients on Principle II: Medicine-Food Collaboration, offering valuable insights to guide the design of integrated dietary and drug interventions in our project.

Through our conversation with Dr. Yuejun Xu, a frontline proctologist, we gained not only a deeper understanding of the pathological mechanisms and clinical treatment strategies for hemorrhoids, but also a profound insight into the importance of humanistic care emphasized by clinicians. Dr. Xu noted that although hemorrhoids are not life-threatening, many patients delay seeking medical attention, missing the optimal window for early-stage (Grade I–II) conservative treatment and eventually requiring surgical intervention.

The patients' accounts offered us a vivid and unfiltered glimpse into the real suffering and psychological strain caused by hemorrhoids. Many shared that, in the early stages, they avoided seeking medical help due to concerns about privacy, feelings of shame, or the misconception that hemorrhoids would resolve on their own-only to end up requiring surgery when the condition worsened.

These voices made it clear to us that if our project is to truly benefit patients, we must confront the issue of stigma.

Through in-depth interviews with patients and clinicians, we obtained valuable feedback that went beyond a purely laboratory perspective.

Based on these insights, we implemented multiple integrations and optimizations in our project. For example, regarding topical drug design, both patients and doctors emphasized that treatment should not only be effective but also user-friendly, discreet, and comfortable. Inspired by this, we expanded the original drug development framework to explore diverse topical formulations, aiming to minimize the psychological burden during everyday use.

Some patients expressed concerns about the rigidity and monotony of daily dietary plans, while others reported irregular eating habits that made it difficult to maintain three meals a day. In response, we revisited the design of our Medicine–Food Collaboration module and developed a more flexible circuit capable of accommodating diverse dietary patterns. This enhancement improves the intervention’s applicability in real-life settings and better aligns it with public needs. The adjustment ensures that our project remains practical, patient-centered, and socially considerate without compromising its scientific objectives.

Cycle 3. Exploring the Phenomenon of Stigma

Through our interviews, we clearly observed that the distress caused by hemorrhoids extends far beyond physical pain. A deeper and more persistent burden arises from the social stigma and feelings of embarrassment associated with the disease. This stigma-induced psychological pressure often leads patients to remain silent about their condition, delaying treatment and avoiding medical consultation.

However, our current research still has certain limitations. Although the questionnaire collected nearly 200 valid responses, the participants were generally well-educated and tended to show higher empathy, which may have introduced a sampling bias. While the in-depth interviews ensured analytical depth and nuanced understanding, the limited sample size makes it difficult to generalize the findings to a broader population. Moreover, since most participants were located in Wuhan, the regional concentration may restrict the representativeness of our results on a national scale.

As our research on hemorrhoid-related stigma deepened, we began to seek a more systematic understanding of its social roots. Guided by the classical theories of Goffman, Link, and Phelan, we explored how stigma is formed, reinforced, and manifested within daily life. These theories not only clarified the underlying mechanisms of social labeling but also provided us with a theoretical compass for understanding patients' psychological burdens.

Building upon these frameworks, we adapted them to the specific context of hemorrhoidal disease-an area long overlooked in social discourse. With this, we aim to reveal how cultural taboos and social silence jointly shape patients' experiences. We plan to expand our investigation nationwide, striving for a more comprehensive and representative picture of hemorrhoid stigmatization in China.

At the same time, our questionnaire offered another key insight: 73.44% of respondents mainly obtain information about hemorrhoids through online self-media platforms. This finding reshaped our understanding of how stigma circulates. Social media, while a major source of health information, can also amplify stereotypes and emotional discomfort through humor, mockery, or misinformation.

Therefore, we shifted our focus toward the online sphere, combining quantitative and qualitative analyses to trace the evolution of harmful narratives, explore their impact on mental well-being, and seek effective ways to communicate health knowledge more empathetically. Through this, we hope to contribute not only to scientific understanding-but also to a more open, respectful, and stigma-free public dialogue about hemorrhoidal disease.

In our study design, we collaborated with the Institute of Psychology, Chinese Academy of Sciences, utilizing their Weibo user dataset maintained since 2010. With the support of Researcher Zhu Tingshao, we collected 112,287 comments containing the keyword "hemorrhoids."

We conducted a qualitative analysis based on the stigma theory framework, which we subsequently adapted to account for the specific characteristics of hemorrhoid-related discourse. In the quantitative phase, the data underwent cleaning, feature extraction, manual annotation, and model construction. Multiple models were trained and compared, among which Chinese-BERT-wwm-ext demonstrated the best overall performance.

Practice Details

Objective

This study aims to systematically analyze public discussions about hemorrhoids on social media platforms (Weibo) in recent years, with a particular focus on stigmatization. By combining qualitative annotation, linguistic feature extraction, and machine learning and deep learning modeling, we aim to reveal the evolving trends of public opinion on hemorrhoids, the linguistic characteristics of stigmatizing expressions, and their underlying socio-psychological mechanisms. The findings are expected not only to advance theoretical research on disease-related stigma but also to provide data support and practical cases for health communication, public education, and interventions to reduce stigmatization.

Data Source

The data used in this study were provided by the Institute of Psychology, Chinese Academy of Sciences. Using a breadth-first search algorithm based on a search tree data structure, the institute constructed a database covering 99,925,821 Weibo users and their public posts from 2010 to 2024. We submitted a data request to Researcher Zhu Tingshao, who filtered the data using the keyword “痔疮” (hemorrhoids) while ensuring data security and privacy, ultimately providing us with 112,287 relevant posts.

Privacy Statement

The database has been approved by the Institutional Review Board of the Institute of Psychology, Chinese Academy of Sciences. Since the research subjects are public Weibo data, no additional informed consent was required in accordance with established research practices (Reavley & Pilkington, 2014; O'Dea et al., 2015; Li et al., 2015). On the Weibo platform, registered users are notified that their public content may be viewed and downloaded, and they can set privacy controls to restrict access. To protect privacy, this study only analyzed public data, and all results exclude any personally identifiable information such as real names or usernames.

Data Cleaning

During the initial screening, we found a large number of advertisements in the comment data. To prevent interference with model training and stigmatization analysis, we removed low-quality texts using a manually defined blocklist. After processing, 53,232 high-quality posts were retained for subsequent analysis.

Data Annotation

Based on prior qualitative research, we established a binary annotation system: 0 represents non-stigmatizing content, and 1 represents stigmatizing content. We manually annotated 2,000 posts for model training and validation.

Feature Extraction

To obtain predictive variables, we used the Simplified Chinese version of LIWC (SCLIWC) to estimate word frequencies across multiple psychologically meaningful categories for each of the 53,232 posts. This yielded a series of linguistic features per post. Standardized values of these linguistic features were then calculated to serve as predictors.

Feature Selection

From the 100 features extracted via LIWC, we removed linguistic and time-related features, retaining the 42 most relevant features related to emotion, cognition, and physical health.

Model Construction and Training

We employed multiple machine learning and deep learning models to classify and compare the stigmatization levels of hemorrhoid-related comments. The machine learning models included Random Forest, Support Vector Machine (SVM), Logistic Regression, and XGBoost. Deep learning models included a Multi-Layer Perceptron (MLP) and pre-trained large language models (GPT2-Chinese-ClueCorpusSmall and Chinese-BERT-wwm-ext).

Random Forest: An ensemble of decision trees with a voting mechanism, reducing overfitting and improving generalization.

SVM: Uses an RBF kernel for nonlinear classification, identifying optimal decision boundaries in high-dimensional space.

Logistic Regression: Uses L1 regularization to constrain feature weights, improving interpretability.

XGBoost: A gradient boosting tree algorithm that optimizes residuals and uses feature subsampling to balance bias and variance.

All models were evaluated with 5-fold cross-validation on the training set, then fitted on the full training set and tested to assess stability and generalization.

Model Parameters

Random Forest: 250 trees (n_estimators=250), max depth=3, min samples per leaf=50, min samples per split=25, max_features='log2'. SVM: RBF kernel, C=20, γ='auto'. Logistic Regression: L1 penalty, C=0.4, solver=liblinear. XGBoost: 250 trees, max depth=2, learning rate=0.01, reg_alpha=5, reg_lambda=35, subsample=0.7, colsample_bytree=0.7, evaluated with logloss.

MLP Model

The MLP model included an input layer, two hidden layers (256 and 128 neurons with ReLU activation and 0.4 dropout for the first hidden layer), and an output layer with two neurons corresponding to the binary stigma labels. Weighted cross-entropy loss was used to address class imbalance, and the Adam optimizer updated parameters.

Pre-trained Language Model Fine-Tuning

We fine-tuned GPT2-Chinese-ClueCorpusSmall and Chinese-BERT-wwm-ext models on the stigma classification task. GPT2-Chinese-ClueCorpusSmall captures semantic and contextual relationships in text, while Chinese-BERT-wwm-ext, trained with whole-word masking, improves word-level semantic understanding and sensitivity to subtle contextual differences. A classification layer was added on top of both models.

Evaluation

Models were compared using Accuracy, Precision, Recall, and F1-score. Pre-trained language models demonstrated clear advantages. Chinese-BERT-wwm-ext excelled in capturing fine-grained semantic differences, while GPT2 effectively modeled contextual logic. MLP achieved performance close to GPT2 when input features sufficiently represented semantics, validating neural network effectiveness on medium-scale tasks. Traditional machine learning models underperformed mainly due to limited feature representation capabilities.

Conclusion

Given its superior performance, the fine-tuned Chinese-BERT-wwm-ext model was used to predict the remaining 51,232 posts. Analysis showed a decreasing trend in stigmatizing posts over time, possibly due to rising educational levels and enhanced platform regulation over the past 15 years.

Yearly variation in the proportion of stigmatizing and non-stigmatizing comments. The x-axis represents years, and the y-axis shows the percentage of each comment type; purple indicates stigmatizing comments, and pink represents non-stigmatizing comments.

Interestingly, certain periods showed sudden spikes in stigmatizing comments. Examination of the original data revealed frequent use of keywords such as “underwear” and “智窗” (homophonous with hemorrhoids in Chinese). Investigation of online news indicated that in June 2012, a rumor circulated that a new CCTV building might be named “智窗,” likely because the building resembled underwear. This incident reflects users’ humorous and mocking attitudes toward hemorrhoids and became a key case for our subsequent public education campaigns.

Monthly distribution of stigmatizing and non-stigmatizing comments in 2012. The x-axis represents months, and the y-axis shows the number of posts; red indicates stigmatizing comments, and yellow represents non-stigmatizing comments.

The analysis revealed that the stigmatization of hemorrhoids on Chinese social media primarily manifests in the following forms:

Stigmatization Forms

Classes	Description
Insult	Usage similar to curse words. Due to the stigma attached to the term "hemorrhoids," it may be used to attack, insult, or curse someone (regardless of whether the person actually has hemorrhoids).
Stereotypes	Associating hemorrhoids with certain behaviors or traits; i.e., forming a fixed and oversimplified impression.
Trivialization	Downplaying the condition, e.g., "Hemorrhoids are just a minor problem" or "It’s only hemorrhoids."
Sardonicism	Using the term "hemorrhoids" to tease or make jokes.
Blame	Assigning personal responsibility for the condition and reproaching the individual, e.g., "Serves you right" or "You brought it on yourself."
Exclusion	Expressions of avoidance or disgust, such as "Don’t come near me" or "Gross."
Shame	Feelings of embarrassment or disgrace, e.g., "Too ashamed to mention it" or "It’s humiliating."

Simultaneously, we summarized the mechanisms underlying the stigmatization of hemorrhoids on social media. We propose that, because hemorrhoids affect anatomically private areas-regions culturally associated with shame and negative connotations-patients inherently experience feelings of embarrassment. This inherent shame renders hemorrhoids particularly susceptible to stigmatization in online environments, where they are often subject to ridicule, mockery, and derogatory remarks. Such social stigmatization reinforces patients' sense of shame, creating a positive feedback loop: the stigmatization of hemorrhoids intensifies personal embarrassment, which in turn contributes to delays in seeking medical treatment.

These findings indicate that subsequent science communication and destigmatization efforts should not focus solely on patients, but also target high-risk populations and the broader public, aiming for systemic changes in awareness and social perception.

It should be noted that the stigmatization of hemorrhoids differs subtly from that of other diseases. For conditions such as depression or HIV, stigma often results in reduced social status, loss of rights, and risks of unemployment, exclusion, or isolation. For appearance-related conditions like obesity or acne, stigma primarily induces strong anxiety in patients. In the case of hemorrhoids, the main adverse consequence of stigma is delayed medical consultation. Therefore, destigmatization efforts for hemorrhoids focus on enhancing public health awareness and encouraging timely medical care. Nonetheless, similar to other diseases, reducing stigma carries significant social and public health importance.

We applied our classification model based on Chinese-BERT-wwm-ext to predict the remaining 51,232 Weibo posts and conducted statistical analysis. The results indicate an overall declining trend in stigmatizing comments related to hemorrhoids, which may be associated with the rising educational level of users over the past fifteen years and the enhanced regulatory oversight on the platform.

Interestingly, we observed sudden spikes in stigmatizing comments at specific time points. Upon examining the original posts, keywords such as "underwear" and "Wisdom Window" ("智窗"，"Zhichuang", homophones related to hemorrhoids in Chinese) appeared frequently. Further investigation of online news revealed that in June 2012, a widely circulated rumor suggested that the newly constructed building of China Central Television might be named "Wisdom Window"(智窗，Zhichuang), due to its "underwear-like" shape. This incident directly reflects the public's tendency to mock hemorrhoid-related topics and has subsequently been incorporated as a key case study in our educational campaigns to illustrate how social and cultural factors contribute to stigmatization.

The results of our social media analysis have been systematically compiled and discussed in depth with Professor Liu Sanming. These insights also serve as a key theoretical foundation for our Education & Collaboration efforts, providing a practical pathway to advance the destigmatization of hemorrhoid disease. To promote destigmatization and spread awareness of synthetic biology, we carried out a series of educational and outreach activities targeting different audiences.

Cycle 4. Consulting Experts for Interdisciplinary Insights

To evaluate the effectiveness of our social media comment analysis in studying stigma, we sought expert guidance. We interviewed Professor Liu Sanming from the Psychological Health Center at Huazhong Agricultural University, aiming to gain insights from a psychological perspective.

Professor Liu's expertise in psychology helps us refine our analytical methods, enhance the accuracy and depth of our study, and identify established approaches for examining stigma and its effects on individuals or groups. Additionally, this discussion provided an opportunity to explore how to better understand and address stigma in future research, ensuring that our work is both scientifically rigorous and socially informed.

During the interview, Professor Liu Sanming highlighted the critical role of education in combating stigma. He emphasized that educational initiatives can change public perceptions of diseases and reduce the spread of negative labels. By disseminating accurate knowledge, we can correct misunderstandings and biases, thereby decreasing social rejection and feelings of shame among patients. Education not only enhances public awareness but also encourages patients to seek help proactively rather than concealing their condition out of embarrassment.

Professor Liu also noted that our drug intervention carries lower risk of shame and social stigma compared to conventional treatments. He pointed out that the Medicine-Food Collaboration concept integrates disease treatment with daily dietary habits, helping patients overcome the psychological barriers typically associated with "medication" or "illness." This approach reduces resistance to treatment and alleviates social pressure related to taking drugs, making therapy more acceptable. Such an implicit therapeutic effect not only improves patient compliance but also helps mitigate potential stigma.

Regarding our social media analysis, Professor Liu described it as a highly valuable and intriguing research direction. Social media reflects public attitudes and emotions toward diseases, revealing the spread patterns of stigma and broader social dynamics. Its rapid dissemination capacity can both accelerate the spread of stigmatizing information and provide a platform for reflection and intervention. By analyzing online discussions, we can gain deeper insights, offering strong support for designing future stigma-reduction strategies.

Based on these insights, we decided to further promote science education initiatives. Through online platforms, public lectures, and other outreach activities, we aim to communicate accurate scientific knowledge and correct treatment concepts to the public. These efforts are intended to challenge stereotypes, reduce social stigma, and encourage patients to seek treatment and support more openly and proactively.

By advancing science communication and education, we hope to gradually foster a more inclusive and understanding social environment, providing patients with greater support and ultimately mitigating the negative impact of stigma on their lives.

Through our in-depth investigation and analysis of hemorrhoid disease, we have come to understand not only its physiological impact but also its profound psychological and social implications. As a private yet highly prevalent condition, hemorrhoids impose not only physical discomfort but also considerable psychological stress and shame due to societal stigma. Throughout our project, while striving to develop effective treatment solutions, we have consistently adhered to a "patient-centered" approach, placing patients' physiological, psychological, and social needs at the core of our design and research efforts.

Looking ahead, we plan to continue public science education initiatives to foster accurate understanding of hemorrhoids and similar conditions, dispel misconceptions, and encourage patients to face their illness courageously and seek timely treatment. Simultaneously, we will expand our social media analysis research, leveraging data-driven insights to further refine intervention strategies and more effectively address societal stigma.

Although our stigma-related investigation has reached a milestone in this project phase, this does not signify an endpoint for patient-centered initiatives. In fact, our team represents only one part of an ongoing collective effort. With the growing engagement of academia, the medical community, and social organizations, the understanding of disease-related stigma will deepen, and corresponding interventions will become increasingly effective. We believe that over time, societal attitudes toward private conditions such as hemorrhoids will become more tolerant and understanding, thereby alleviating patients' psychological burdens.

In the iGEM competition, we have taken an important first step, yet our attention to this issue will never cease. Moving forward, we remain committed to advancing social awareness of hemorrhoids and related diseases, working hand in hand with all stakeholders to build a society that is more inclusive, supportive, and compassionate toward patients.

Epilogue

In order to ensure that rational thinking is implemented throughout the project, we decided to use the SWOT analysis method in the project implementation.

Throughout the project process, we integrate information gathered from surveys, discussions, and interviews into a SWOT matrix. This allows us to rationally analyze the challenges facing the project and continuously identify potential actions based on opportunities. We aim to eliminate or mitigate weaknesses, avoid threats, and increase or maintain project strengths.

In this SWOT analysis table, we recorded both existing and newly added nodes in each category as the project evolved, while removing the weaknesses we have already overcome.

Looking back on our outreach journey, we grew through mutual learning in our whole-grain education activities, which led us to select black rice as a representative case for our Medicine–Food Collaboration (Principle II). The "For Her Health" Mother's Day campaign provided two-way communication that strengthened our determination to develop pregnancy-compatible therapeutics (Principle I. Precision Therapy) and laid the groundwork for subsequent stigma analysis (Principle III. Patient-Centered Approach).

Upholding the concept of Patient-Centered Approach (Principle III), we recognized from our stigma analysis that public education plays a crucial role. Therefore, in the later stages of our project, we carried out extensive outreach and collaborations-details of which can be found on the "Education & Collaboration" page.

These efforts collectively trace the evolution of our project's spirit-from listening to resonance, and from resonance to action. Through every encounter, we realized that IHP is not a one-way process of interviews and feedback, but a continuous dialogue where ideas and reality shape each other. Each conversation made the principle of "putting people first" more tangible, and transformed science from a mere instrument into a force that responds to genuine pain and societal needs.

Now, as we look back, what we see is not just the completion of a project, but a journey of drawing closer to people. We believe that only when science moves in harmony with life-and research with humanity-can innovation truly take root.