Human Practice

YiYe-WuHan iGEM's 2024 project, the early treatment of colorectal cancer, integrates expert knowledge and addresses the public's needs and vision for colorectal cancer at every development stage. Our commitment to Human Practices (HP) centers on critically evaluating the ethical and global impact of our synthetic biology project. We have focused on improving accessibility to colorectal cancer treatment. Insights from the public, industry experts, and cervical cancer specialists have guided our project and product enhancement. Below, we present a comprehensive record of our HP interactions.

Firstly, the questionnaire was released to find out the general public’s understanding of colorectal cancer. Respondents were required to mark their degree of understanding about colorectal cancer themselves and answer questions about common knowledge of colorectal cancer, such as the age of high incidence and potential risk factors.

Utilizing the mechanism of the siRNA and TEAD4 mentioned above, our project designs the siRNA to downregulate the expression of the TEAD4 in the colorectal tumor cell SW480. Theoretically, when the siRNAs were transfected into SW480 cells, the TEAD4 expression was inhibited. TEAD4 expression could affect downstream Hippo pathway. Therefore, when SW480 cells were treated with siRNAs, the proliferation, migration and invasion ability were inhibited. The tumor cells tend to lose the cancer cell character after siRNA treatment, which are expected to achieve favorable curative effect in clinical practice .

In addition, this questionnaire was designed to disseminate essential knowledge about colorectal cancer. This objective was achieved by providing correct answers to the questions. Facts about colorectal cancer that needed attention were directly listed in the questions, and participants only needed to check whether they knew the information instead of providing an answer. This method allowed participants to absorb knowledge they previously lacked.

Last but not least, we aimed to raise awareness about colorectal cancer. We informed every participant about the importance of regular health examinations for early diagnosis and treatment of colorectal cancer and encouraged them to adopt a healthy lifestyle to prevent it.

All these three questions were designed to inform participants about some of the conditions of colorectal cancer and to give them a primer of knowledge. Through these three questions, it was found that the public still has a certain understanding of colorectal cancer, but because it was not specifically studied, the issue of colorectal cancer like those groups of people will not be well understood and not have a comprehensive knowledge. This shows that certain popularization is very important.

Question 1: What do you think are the symptoms of colorectal cancer
Question 2: Which option do you think makes people vulnerable to colorectal cancer?（Male or Female）
Question 3: What kind of people do you think get colorectal cancer?

QUESTION: Which of the following practices do you think would prevent colorectal cancer?

According to the data table, among the effective practices for preventing colorectal cancer, regular screening is the most highly esteemed with a high percentage of 97.06%. This was followed by adhering to regular exercise (86.27%), maintaining an active lifestyle (84.31%) and eating more fruits and vegetables (79.41%). On the contrary, the percentages of regularly eating foods high in salt and sugar (4.9%), eating more processed meat (7.84%) and avoiding exposure to environmental risk factors (53.92%) were low. The percentage of smoking and alcohol cessation was 63.73%. In this question often eat foods high in salt and sugar, eat more processed meat these two options are wrong although the percentage of choices is very small but still some people choose it, which shows that there are still some misunderstandings about how to prevent it, and need to correctly popularize the science.

QUESTION: Which of the following do you think is a treatment option for colorectal cancer

According to the data table, among the treatment options for colorectal cancer, siRNA-targeted therapy has the highest percentage of 73.53%, followed by tumor resection and chemotherapy with 70.59% and 50%, respectively. High-frequency electrocoagulation resection, endoscopic submucosal dissection and mucosal resection were 43.14%, 39.22% and 36.27%, respectively, and radiation therapy had the lowest rate of 32.35% . Through our participants our topic siRNA-targeted therapy science, we all have an understanding of this, and can also be seen from this everyone still believe in the most common and most common surgical resection methods.

The participants demonstrated a high level of awareness of colorectal cancer and an understanding of the importance of prevention and screening. However, they also exhibited certain doubts and expectations regarding the novel treatment option siRNA. It can be posited that the strengthening of awareness of prevention and screening of colorectal cancer, while balancing the introduction of the advantages and risks of novel therapeutic options, may prove an effective method of improving public awareness of colorectal cancer and acceptance of novel therapeutic options.

At the end of July 2024, our team leaders Yuhan Yang and Qiancheng Yu visited the Wuhan Institute of Biotechnology ( Wuhan Bio 武汉生物技术研究院) in the Optics Valley of China. The Wuhan Bio has six prominent research centers that offer a wide range of biology science, including biotechnology, biomedical science, biological agriculture, biological environment, bioenergy, and bioeconomics, to strengthen. It’s the first new industrial technology research institute in Hubei, which focuses on the construction of industrial support platforms, the introduction of scientific talents, and the commercialization of scientific and research findings.

We mainly visited the center for biomedical science which facilitates both fundamental science and applied research. It covers a wide range of diseases to further understanding of pathophysiology and search for novel druggable targets, which also develops cutting-edge technologies and assays to aid understanding of basic science and aims to improve public health and treatment strategies. We thought the development of biomedical research and health innovation are inspiring for our project which aims at constructing novel biotherapeutics through siRNA for improving patient treatment of CRC.

Especially when we had meaningful and deep conversations with Dr. Chen Xi and shared our ideas with him. Dr. Chen inspired us to gain insights into the practical implications of our project. We realized that the promising drug for cancer treatment is inseparable from clinical trials, and drug discovery from the laboratory into the clinic for patients in need, we still have a long way to go.

During the development of our project, we prioritized creating a responsible and beneficial project and work process that accorded our core values. We achieved this by maintaining an open-minded approach and refining our understanding, design, and actions. Engaging in constructive interviews with experts in the field—researchers, doctors, and stakeholders—challenged our ideas and guided us toward making our project safer, scientifically accurate, and ethically sound.

2024Yiye-Wuhan's project is to prevent cancer cells from increasing in value by interfering with the high expression of TEAD4 in the cells of colorectal cancer patients through the use of siRNAs. 27.07.07, two members of the team went to Spectrum Zonghe (Wuhan) Life Sciences Co., Ltd. and interviewed with the general manager of the company, Mr. Chen Xi.

First of all, we introduced our project to Mr. Chen Xi about our research on the use of small interfering RNA (SiRNA) targeting TEAD4 expression as an emerging drug for the treatment of Colorectal cancer. At the same time, we also learned that Puduzhonghe is doing related work through proteomic analysis.

Secondly, Mr. Chen Xi introduced to us the importance of proteins to human beings. We learned that the occurrence of all diseases, health or not, is closely related to the abnormal expression of proteins in the body, so basically all the targets of drugs are proteins are the types of drugs. He also popularized several emerging drug therapies: small molecule drug therapy, large molecule drug therapy, cell therapy, and gene antibody therapy. Although these therapeutic modalities require different types of drugs, their targets are all proteins.

As for the challenges faced in protein analysis, Mr. Chen Xi believes that the sample size is not enough, because the samples are clinical human samples, and then there may be a strong individual difference between a person and a person, how to minimize the individual differences, then it requires thousands of samples to be large enough to eliminate some individual differences. Although both are cancers, maybe both are lung cancers, both are this kind of cancers, the expression of many proteins in the body of the two people is different, how to eliminate the non-individual differences or non-specific signals brought about by the individual differences among such signals in the messy signals, then it requires a variety of means of statistical analysis. And not only the sample size should be large, but also a sample corresponding to very strict clinical information, and then based on this clinical information to eliminate some of the confounding factors before doing experiments, perhaps at this level, or to do a match between the samples, to eliminate some of the factors that may bring confounding factors to the final judgment of such a result in advance.

From Mr. Chen Xi's sharing, we know that making drugs is actually a long process, and it is necessary to correct one's own position. Different people have different abilities and resources, and it is difficult to do something from the beginning to the end, and do it all down, which is why so many of these enterprises making drugs have failed because they do not know their own position. They start with a very ambitious goal of treating some kind of cancer and benefiting the patients, but in fact they don't have the ability to expand downstream.

Finally, Mr. Chen Xi expects to the researchers who are doing scientific research, everyone needs to put themselves in the right position, and don't go beyond the scope of their ability to do something they are not good at when they are well positioned. Often a person's failure may be from this point onwards, sometimes too much desire, but your own ability does not match your desire, this is the source of pain. Just get down to what you're best at and do it well, each in their place, if there is to be discipline it is each in their place, this is discipline, this is the most real opportunity.

After interviewing Dr. Liu Weicheng, we gained a certain understanding of the general treatment for colorectal cancer. To gain a more comprehensive and multi-perspective understanding of this global third most prevalent disease, we interviewed Dr. Cheng Yifeng, Associate Professor in the Gastrointestinal Surgery Department at the Tongji Medical College of Huazhong University of Science and Technology, who has extensive treatment experience in China, to discuss our proposal in more depth.

In clinical practice, Dr. Cheng believes that for most patients diagnosed at an advanced stage, the conventional treatment approach involves a series of standard methods such as surgery, chemotherapy, and radiotherapy, or using ancillary therapy and conversion therapy if the cancer cells have metastasized (without any complications). Once treatment successfully reduces the stage of the cancer, conventional surgical resection can be employed to remove the tumor and eliminate the cancer. For early-stage colorectal cancer patients, treatment is simpler and usually involves endoscopic surgery. This aligns with Dr. Liu Weicheng's earlier remarks that the treatment costs for early-stage patients are significantly lower compared to those for advanced-stage patients, which is proportional to the complexity of the treatment methods. However, since siRNA technology is still immature, it cannot yet be applied to clinical patients and remains a long way from clinical application.

Regarding the possible causes of colorectal cancer, Dr. Cheng believes that its occurrence may be related to dietary structure and genetic diseases. Analyzing the data, Dr. Cheng commented that colorectal cancer is relatively rare in China and East Asia, which is somewhat related to the gradual change in the Asian diet. Historically, China mainly consumed carbohydrates, with less meat and vegetables, and this nutritional deficiency may have contributed to the silent occurrence of colorectal cancer. In recent years, with the continuous rise in China’s economic strength, living standards, and happiness index, people are paying more attention to the nutritional value and scientific dietary balance. Dr. Cheng believes that the increase in the proportion of meat in the Chinese diet has somewhat inhibited the development of colorectal cancer among Chinese people. However, this trend is not uniform globally. For example, the incidence rate in the United States is significantly higher compared to China, but the proportion of meat in their diet is not lower than that in China. This might be indicative of the influence of dietary nutrition on the incidence of colorectal cancer. Additionally, parents who have had or currently have colorectal cancer may have some impact on their children, potentially increasing their risk of developing colorectal cancer.

Finally, in terms of colorectal cancer prevention, Dr. Cheng advocates the "preventive treatment" approach, i.e., "treating before the disease occurs," and promotes regular screenings. Even though the current effective method for screening and preventing colorectal cancer is limited to colonoscopy, and despite the public's negative impression of "colonoscopy" and "gastroscopy," Dr. Cheng still considers colonoscopy as the preferred method for prevention and screening. Firstly, colonoscopy is not as painful as imagined; with current technology, it is generally painless. After anesthesia, patients only feel a slight drowsy sensation, and the colonoscopy is over quickly. Dr. Cheng has personally undergone a colonoscopy and found it painless and quick. He recommends that people over the age of 40 undergo a colonoscopy during their health check-ups, and if no issues are found, repeat the test every five years. If minor issues are detected, the frequency of colonoscopy should be increased. Additionally, frequent changes in stool characteristics and abdominal pain can also be indicators of colorectal cancer. Dr. Cheng advises that if such symptoms occur, high-frequency screenings at a hospital are necessary.

Colorectal cancer, existing as the cancer of second highest presence in cancer patients and the third highest mortality rate, however, hasn’t been noticed by most of the population. What people preoccupy with are always those of the highest morbidity such as lung cancer and breast cancer but neglect the ubiquitous presence of colorectal cancer around us. According to the WHO, approximately 150,000 people each year are diagnosed with colorectal cancer in the United States, and most of the patients are found carrying colorectal cancer in their middle stages and final stages of colorectal cancer. It is commonly held that the level of medical treatment to the middle-final stages of cancer can’t even be compared with the level of medical treatment to the early stage of cancer because of its extreme toughness. It is people’s neglect and omission towards colorectal cancer and their health conditions that created substantial tragedies. In order to alleviate the economic pressure that colorectal cancer patients’ families have to withstand as well as to advocate for the awareness of colorectal cancer, our iGEM group, Yiye-Wuhan, initiated research of a novel colorectal cancer therapy using siRNA to silence TEAD4 protein. The principle of this therapy is that through binding of siRNA with dicer protein, RISC forms and thus dissects the mRNA of TEAD4 protein, which inhibits the functioning of the hippo pathway that is responsible for the proliferation of colorectal cancer cells, thus reaching the effect of cancer treatment. In order to gain more prospects and cognition towards our research, we interviewed Dr. Liu Weicheng from the Department of Colorectal and Pelvic Floor Surgery at Zhongnan Hospital of Wuhan University, Dr. Cheng Yifeng from Tongji Medical College Affiliated Union Hospital of Huazhong University of Science and Technology, and Mr. Chen Xi from Pudu Zhonghe Wuhan Life Science and Technology Co. and decipher the treatment of colorectal cancer at the front line. Moreover, these specialists spoke from their own expertise and gave us precious messages as to the perception of experts toward siRNA silencing target therapy.

The primary treatment modalities are surgery, radiotherapy, chemotherapy, and immune targeting. Surgery is the most direct treatment option, as it is the only approach that can effectively address locally advanced and recurrent colon tumors. While other modalities may delay the disease, they cannot achieve a cure. Ultimately, surgical intervention remains the mainstay of treatment. The first reason is that surgery can provide the most direct treatment for patients, including those with advanced disease. Following surgery, patients can achieve a five-year disease-free survival rate of over 60%. The second reason is that, for patients with advanced disease, chemotherapy, radiotherapy, and immune-targeting are ineffective. Surgery remains the only option for these patients, and surgical technology has advanced to the point where minimally invasive surgery is the norm. The extent of damage to the patient's body is less than that which was previously observed. In light of the prevailing medical perspective, surgical intervention represents the most direct and significant treatment option for CRC.

Surgery is performed for stage I colorectal cancer, the lesions are small and the cancer cells have not yet spread to the surrounding tissues. The approximate cost is 60,000~70,000 yuan, and most of the total cost can be reported. Basically, all the costs of a patient discharged from the hospital for a colon tumor should be about 60,000 yuan together. Wuhan City health insurance, you have to pay about 20,000 yuan by yourself, but not more than 30,000 yuan is enough. In addition, many people only need about 10,000 yuan after the reimbursement rate is high. For locally advanced and recurrent cases, where the tumor is large and spreads to the surrounding tissues and lymph nodes, the national cost is now uniformly about 150,000 yuan. That's why there is also hope for better drugs in colorectal cancer. For example, after the success of siRNA therapy, this kind of old late-stage recurrence, if not cut such a wide range of tumors, its cost can certainly be reduced, but surgery is still irreplaceable as one of the treatment processes. Prevention of colorectal cancer requires a balanced nutritional intake, regular meals, and smooth bowel movements, and people over the age of 40 are advised to have regular colonoscopies with a professional doctor to prevent the disease.

Yiye-Wuhan also asked about the measures that can be taken to comfort and care for patients' psychology, Dr. Liu suggested that the essence of solving this problem is to improve the surgical technology, without good surgical technology, the care is one-sided or even ineffective. For example, nowadays we can cure many cancers that could not be cured before, instead of verbally promising the patients that they can be cured, Dr. Liu also mentioned that the research on tumors is actually to look for new treatments, which is the core of the problem, and the care must be built on the basis of solving the problem, and the care will be ineffective if it can't solve the problem.

According to Dr. Liu, earlier stages of CRC can be fully resected by surgery, but later stages of the cancer are harder to deal with. His contribution to CRC surgery mainly focuses on this challenge, where he and his team were the first few who mastered the resection of later stages of CRC. First, the challenges of CRC are hard to overcome mainly because of its anatomy, where the tumor lies just beside reproductive organs like the prostate(male), or the uterus(female), and other crucial parts of the digestive system such as the anus. Although Dr. Liu has conducted surgeries where he preserved the patient's anus and most of their colon and successfully removed the tumor, he at the same time said that there would be a significant improvement in the quality of the surgery when there is control over the growth of the CRC tumor, especially when there is shrinking in size of the tumor. SiRNA regulations of downstream oncogenes can be a considerable therapy that achieves these results. So, siRNA can act as an ancillary therapy that helps greatly in minimizing the damage and shrinking the challenge of the surgical resection of CRC tumors. Not only in CRC, but multiple cancer also shares the same kind of pathology, so siRNA can also be involved in multiple kinds of cancer treatments.

SiRNA is still in the clinical trial stage, and the general therapeutic effect is still not clear, and the cost of the experiment is also a problem that needs to be solved. A drug needs a lot of steps from research and development to the market, the formula needs to be improved and adjusted several times, the structure of the lead compound is optimized in vitro experiments, and then it enters the clinical trial stage, and the new drug can be registered after the third phase of clinical treatment. SiRNA is a kind of highly specific gene therapy, which can avoid side effects such as radiotherapy and chemotherapy in clinical treatment, and can also avoid the risk of surgery, and has extremely huge therapeutic potential and value, which can be called revolutionary therapy.

The role of psychological support in oncology is huge as the same with the early diagnosis and treatment of cancer, like what we are doing now. It is essential to consider our project is very meaningful, but the early and appropriate psychological and emotional support can also improve the health and wellbeing of people affected by cancer.

Dr Meng mentioned that the World Health Organisation (WHO) defined health as: “a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity”1. Furthermore, “mental health is defined as a state of well-being in which every individual realizes his or her own potential, can cope with the stresses of life, can work productively and fruitfully, and is able to make a contribution to her or his community”.

In the conversation with Dr. Meng, we got to know that cancer and its treatments have the potential to significantly impact on mental health, physical health and socio-economic status in multiple ways. Psychological distress is a common and understandable response to a diagnosis of cancer, acute treatment and living with and beyond cancer. Most people will use a variety of resources to cope including their own inner emotional resources, the guidance of trusted healthcare professionals and external support systems such as family, friends. Increasingly social prescribing and the arts have demonstrated a significant impact on health and well-being too⒉.

However, it is important to consider the psychological factors in cancer more broadly than narrow diagnostic definitions of clinical anxiety and depression. Consideration of the way that psychological obstacles can impact on whether ‘physical’ cancer rehabilitation is successful is also essential in improving patient outcomes and quality of life.

Complete dialogue with Dr Meng, we now understand that caring for the patients’ inner feelings plays a crucial role in clinic cancer treatment. Meanwhile, it’s also very important for doctors to keep the patients in an optimistic mood. Even if the patient is in his (or her) last moments, we should give our best to relieve the pain and keep patients in positive mood. In the end, it is essential to respect the patient's dignity.

1 World Health Organization (2006) Constitution of the World Health Organization. Available here: http://www.who.int/about/mission/en/

2 All-Party Parliamentary Group on Arts, Health and Wellbeing (2017) Creative Health: The Arts for Health and Wellbeing (Inquiry Report). Available here: http://www.artshealthandwellbeing.org.uk/appginquiry/Publications/Creative_Health_Inquiry_Report_2017.pdf