Human practices
From the world, back to the world.
Since our project is to explore a new drug delivery system for polypeptide drugs, we need to fully understand the current use of polypeptide drugs in hospitals and related treatment diseases, and select appropriate drugs to carry them, so as to improve the delivery of related drugs and thus improve the efficacy. To this end, we first preliminarily screened several departments of the hospital that are more likely to realize the application of the product for field investigation. These department include gastroenterology, gastrosurgery, and dermatology. Further, in order to better understand the needs of society so that our projects can be adapted to the needs of stakeholders, we also have in-depth communication with the medical insurance bureau, special clinics and other departments. These interactions with stakeholders have made us more aware of the importance of achieving stable drug release.
As the iGEM community says, "Human practices matters at every stage of your project". Therefore, in order to ensure that our behavior is responsible to the society, and at the same time, we can fully understand the needs of the society in the process of project implementation and improvement, so as to promote us to make useful contributions to the society, we discussed our concept of human practice (HP) activities at the beginning of the project. Ultimately, we took inspiration from the holistic reflective model adapted from Gibbs, Johns and Cranton [1].
During our iGEM journey, we went through the concept model twice, showing in the right figure. According to this concept model, we first recognized the flaws in the project, then communicated the issues to relevant stakeholders, and subsequently understood the opinions and ideas of others at different levels. Finally, we would give feedback on the information we obtained to enhance the project.
While implementing the project improvement cycle, we were also concerned about some social problems that may arise from the project. Specifically, as illustrated in the right figure, while addressing the project issues, we also emphasized the importance of humanistic care in medical treatment, based on the concept of people-oriented and compassionate patient care. Moreover, we focused on the social prevalence of missing patients with chronic diseases. Through education and awareness, we guided children in dealing with the challenges they may encounter in life, while simultaneously enabling them to appreciate the allure of synthetic biology. Throughout our iGEM journey, we gained a more comprehensive and more holistic perspective of the problem we are trying to solve.
During our iGEM journey, the people we talk to include:
Figure 1. The HP activity conceptual model
At the beginning of the team formation, we brainstormed the project. Combined with the current situation and possible social needs, we have proposed many ideas, including real-time monitoring of thyroid hormone levels in the body, using engineered bacteria to synthesize selenium, improving lactose intolerance, and so on.
Through the process, we gained knowledge about the advantages and disadvantages of polypeptide drugs. Polypeptide drugs themselves have the advantages of high specificity, high efficiency and so on. From the development of the peptide drug market, it can also be seen that the demand for peptide drugs is increasing.
However, we were aware of the key limitations of peptide drugs for therapeutic use, one of which is the difficulty of delivery. So we thought that focusing on the delivery of polypeptide drugs and trying to improve this problem would be responsible for society's needs and stakeholders.
Since we were studying microbiology, the function of the toxin secretion system of bacteria to deliver virulence factors coincided with what we think of as delivering drug proteins. This led to our subsequent communication with Professor Dong.
Meanwhile, we wanted to know whether the public's views and preferences on the use of polypeptide drugs coincided with our ideas, so we designed a questionnaire on the preference of common drug use, distributed through the Internet and collected data.
Through the questionnaire, we were pleasantly surprised to find that the public's ideas matched our own. Conventional oral administration, as shown in Figure 1, was considered the most ideal mode of administration by the overwhelming majority of investigators. However, after learning pharmacology, we know that the oral effect of many drugs is relatively poor, and there is a reason for the elimination of the first pass, that is, part of it will be absorbed by the gastrointestinal tract, the liver, etc., so that the efficacy is greatly reduced. At the same time, as shown in Figure 2, nearly two-thirds of the respondents considered the effectiveness of medication to be the most important of several aspects. In such cases, there is a conflict between the public's demand for the effectiveness of medication and the results currently provided by oral medication. If we can explore a new way of administration to avoid the weakening of the efficacy after oral administration, we can theoretically resolve the contradiction between the current delivery method and the efficacy of polypeptide drugs.
The results of this questionnaire affirm the feasibility of our idea and show the significance of the realization of the idea for society. This means we can continue to explore and build on our projects.
Figure 2. The big blue letters in the middle of the illustration are oral
Figure 3. The number of people selected in five aspects is shown graphically. 70.33% thought that the importance of drug efficacy ranked first
Before the discussion with Professor Dong, an expert in the study of bacterial type 6 secretion systems, we had reviewed a lot of literature to verify our idea. After discussing with Professor Dong, we settled on the idea of using type 6 secretion systems to carry drug proteins. At the same time, we chose Vibrio cholerae and Pseudomonas aeruginosa as engineering bacteria. Because the previous study of these two bacteria is more thorough on their type 6 secretion systems. In the communication with Professor Dong, we learned that the type 6 secretion system is excellent as a drug delivery system: the effector factors are folded before secretion, so it can ensure that the drug protein is modified before secretion. Professor Dong also continued to provide us with a lot of advice and help and was willing to let us carry out experiments in his laboratory.
Figure 4. Online meeting with Professor Dong
Because our ultimate goal is to use the type 6 secretion system to achieve polypeptide drug delivery in the human body, what role bacteria play in the human body and what impact bacteria can have on the human body are questions we need to understand. So we thought it would be very helpful to consult a microbiology expert at a medical school. We asked Professor Yang Liang of the School of Medicine at Southern University of Science and Technology. In this consultation, Prof. Yang answered our questions.
First, we raised our doubts about the bacteria we selected, that is, whether the bacteria introduced from outside would disrupt the homeostasis of the human flora. Prof. Yang told us that non-human bacteria are likely to destroy the homeostasis of human flora. For this problem, Prof. Yang proposed a novel idea, that is, to extract the bacteria that exist in the lesion itself in the human body for transformation. There are many benefits, not only to avoid the problems caused by non-own bacteria, but also to ensure that bacteria can quickly adapt to the environment and grow better when entering the body.
In addition, whether bacteria can correctly fold complex polypeptide drugs is also a concern. Prof. Yang believed that such problems have been existing and were something we needed to think about before choosing drugs to express.
Figure 5. Offline conversation in Professor Yang's office
Since iGEM prohibits the use of humans for experiments and we cannot obtain human tissue, we have proposed alternative methods for the idea of extracting bacteria from in situ. After confirming with PI, we decided to knock out the virulence factor of the bacteria as much as possible in order to reduce the immune response of the body to the bacteria. At the same time, we also found in some articles that the type 6 Secretion System can normally express protiens in harmless bacteria such as E.coli, so we planned to establish a model with Vibrio cholerae and Pseudomonas aeruginosa first. If the model was successfully established, we would try to transfer the system into other harmless stains to further ensure safety [2]. For the problem of protein folding, we specified the selected drug protein to be less than 40kDa, within this range, bacteria can express the correctly folded protein.
After confirming the construction of the model and how to handle it, we need to consider what therapeutic drugs to carry and what diseases to treat. It matters to the stakeholder. Considering the potential uses of our product and the current disease situation, we decided to start with a number of diseases that require treatment with polypeptide drugs such as gastrointestinal diseases and tumors. And we were honored to interview Dr. Zhang, an expert in gastroenterology and chief physician living in the coastal area, the City of Xiamen.
As the deputy head of the inflammatory enterology Group of the Gastroenterology Branch of Xiamen Medical Association, Dr. Zhang has a deep knowledge of digestive tract diseases. At the same time, we were also honored to interview the Department of Pharmacy clinical Pharmacy Group leader, Xiamen Pharmaceutical Society Clinical Pharmacy Branch member Dr. Yan; Associate Professor of Xiamen University School of Medicine, Member of Xiamen Children's Chronic Disease Management Center, Director of the ninth member of the Pediatrics Branch of Xiamen Medical Association, Dr. Yao; Fujian Medical Association Cancer Medicine Branch of the first committee Standing Committee, Fujian Anti-cancer Association of the first and second lymphoid tumor professional committee member, Dr. Ye.
During the communication, the four experts all affirmed our project and believed that it has great potential in future medical treatment. They have been of great help to our project.
Figure 6. Communication with doctors in the First Affiliated Hospital of Xiamen University
Thanks to this consultation, we have initially identified several drugs suitable for delivery and having great potential for use in the treatment of diseases.
Teduglutide is a recently approved glucagon-like peptide 2 (GLP-2) analogue for pediatric short bowel syndrome (SBS) patients older than 1 year of age. Short bowel syndrome is a leading cause of intestinal failure, and many pediatric SBS cases develop necrotizing enterocolitis, gastroschisis, intestinal atresia, and volvulus shortly after birth [2]. We learned, however, the drug requires a subcutaneous injection once a day. The pain associated with kits currently on the market with larger needles will reduce compliance. In addition, the body's changing hormone levels can also affect the effectiveness of the drug, and an auxiliary device is needed to adjust the dose according to the body's hormone levels. Therefore, we believe that modifying drugs is appropriate and improving them will benefit the quality of life of the people concerned.
Somatotrophin, a growth hormone injection, is indicated for the treatment of pediatric patients with growth disorders due to insufficient secretion of endogenous growth hormone. However, 6-7 subcutaneous injections per week are a painful process for children. In addition, the protein structure of growth hormone is relatively simple, so we believe that it is also an important candidate for drug delivery.
In addition, thanks to the suggestions of Dr. Ye, we also paid attention to the pro-apoptotic peptides KLA (research stage) and Parkin (research stage), both of which showed great potential in anti-cancer. Although still in the research phase, all of them need to work inside the cell. Therefore, we also included these two peptides in our onboard candidates.
In addition, Dr. Zhang suggested that the treatment of chronic diseases would be an important application area of the product. For patients who need to take medication regularly for a long time, our program will significantly reduce the number of times patients take medication, while also improving patient compliance. Dr. Zhang mentioned that the problem of loss of follow-up for chronic diseases is still a concern, and many patients do not carry out regular review and medication because of the trouble of repeated visits to the hospital. This has greatly inspired our work of human practice, and we have designed a set of solutions to improve the accessibility of patients with chronic diseases.
Following our original HP philosophy, we focused on other areas. This included a tour of hospital wards, from which we learned that hospitals reserve the rooms with the best views for patients. This reminds us of humanistic care. In addition, we have introduced doctors to our project and synthetic biology.
Figure 5. Wards visiting and distribution of brochures
When our project was making initial progress, we were honored to be invited by the iGEM team of Shenzhen University to participate in the 7th South China Regional Meeting. In this meeting, we presented our results to many teams in South China and it was well received. In this meeting, we communicated with many teams and got a lot of inspiration for our subsequent projects.
Figure 6. Interaction with other teams
We chose Chengdu, where the food is spicy and stimulating. We were curious about whether there were differences in gastrointestinal diseases in areas with different dietary habits, so we once again sought gastroenterologists to understand the prevalence of gastrointestinal diseases in Sichuan.
Dr. Zhang is an expert in digestive tract diseases. Through communication with him, we learned that spicy and stimulating food is not necessarily directly related to gastrointestinal tract diseases, and there are many factors that affect the incidence of digestive tract diseases. For some common gastrointestinal diseases, different regions have the possibility of occurrence. For the treatment of digestive tract tumors, Dr. Zhang mentioned that if long-term safe drug administration can be achieved clinically, it can bring great value to the treatment of chronic diseases/tumors in the gastroenterology department.
Figure 7. Communication with Director Zhang in the consulting room
We did not look for other drugs for the treatment of digestive tract diseases, given that we had previously obtained relevant drugs. However, in the process of communication, Dr. Zhang believed that our project has the potential to be used for the delivery of other drugs such as Tenecteplase for the treatment of acute myocardial infarction and minihepcidins synthetic peptides. The doctor suggested that we could ask more departments to achieve a wider range of applications.
After discussion, we decided to go to the dermatology department and ask about some suitable medications. We immediately contacted Dr. Ying, the director of the Institute of Dermatology of Sichuan Provincial People's Hospital. Since Dr. Ying was busy with his work in the clinic, we took advantage of his spare time to consult about peptide drugs for skin treatment. We asked Dr. Ying about the use and efficacy of several peptide drugs commonly used in dermatology, such as antibiotics represented by antimicrobial peptides.
We learned that polymyxin was used the most and antimicrobial peptides were used less. After that, Dr. Ying briefly introduced to us the treatment strategy of dermatology infection. Based on the current situation of the beauty industry fire, we asked the dermatology cosmetic direction drug peptides use methods and prospects. Finally, for melanoma in skin cancer, we asked Dr. Ying about the difference and comparison between the new and old drugs in terms of mechanism of action, efficacy and so on.
Figure 8. Communication with Director Ying in the consulting room
This consultation with Dr. Ying, we have gained more is some perception. We recognize the importance of offline research. Although many drugs can be found on the Internet, there is still a big difference between the information on the Internet and the actual situation in reality. In addition, we also learned that many targeted drugs can be entered into health insurance through special clinics. Due to the high price of some drugs, especially new anti-tumor drugs, the medical insurance system has greatly reduced the cost of treatment that patients need to bear. This led to our the next step of investigation.
As a matter of principle, we strive to explore the benefits we can make to society. Through discussion, we considered the problems found in the last human practice activity, so we determined the main purpose of this social research activity: to understand the relevant system of medical insurance, the mechanism of chronic disease clinic and the general process of drug manufacturing. These help us to explore what our products can contribute and potentially use.
In Unit 1, we learned that the problem of missing people with chronic diseases still exists. With the idea of better making our products available to the beneficiaries, we interviewed Dr. Wu, director of the endocrinology Department of Chengdu Xinhua Hospital, affiliated to North Sichuan Medical College, in the local area. Dr. Wu is not only an endocrinologist, but also in charge of chronic disease outpatient field, and is very familiar with related aspects.
Through the consultation with Dr. Wu, we learned about the mechanism of chronic disease clinic, as well as how to manage and promptly remind chronic disease patients to take medicine regularly for medical consultation. The most important thing is that we learned from the conversation that although relevant policies have been introduced to provide convenience and preferential treatment for patients with chronic diseases, and some measures have been set up to remind patients with chronic diseases to get medicine and return to the hospital regularly, which has solved the problem of patients getting medicine regularly to a certain extent. But other factors that are important to control the development of chronic diseases, such as regular medication at home and regular physical check-ups, are not well regulated. It is important to take medication regularly and go to the hospital for regular check-ups.
In terms of the treatment of diseases, Dr. Wu affirmed our project, believing that this can greatly reduce the number of patients taking drugs, so it can also reduce the inconvenience caused by patients taking drugs multiple times. He suggested dulaglutide, an injection used to treat type 2 diabetes. The drug, which currently requires weekly injections, is a suitable candidate for delivery.
Figure 9. A photo with Director Hu outside the outpatient department of the hospital
After understanding the relevant situation, we realized that solving the problem of chronic disease treatment is not only to improve the drug, but also to improve the cognitive level of patients and involve many aspects of policy, system and management.
Through the discussion of the whole team, we decided to put forward our solution from the level of communication between medical staff and patients as well as the level of education for patients with chronic diseases, so as to make efforts to improve the problem of lost visits for patients with chronic diseases.
In addition, we intend to present some of our ideas and solutions at the level of chronic disease data management software. Through the inquiries to the affiliated Hospital of North Sichuan Medical College and the Hospital of Southern University of Science and Technology, we learned that some departments have chronic disease information management systems for their departments, including the use of software to know the time of patients' last drug withdrawal and send messages to remind them when the next drug withdrawal is approaching. However, we think there are some areas that could be improved, which would be useful for doctors to understand their patients' regular visits and patients to understand relevant information.
In China, medical insurance is one of the five social insurances, which belongs to the social welfare of the whole people. It can reduce the burden of medical treatment for the masses, improve people's well-being, and maintain social harmony and stability [4]. Peptide drugs account for a large portion of health insurance funding, and our project is also a new drug development. We believe that through the investigation of the medical insurance bureau, we can deeply understand the mechanism of the inclusion of new drugs in the national medical insurance and the determinants of the inclusion of drugs in the medical insurance, so as to try to explore the advantages of our products. We consider this behavior socially responsible.
Through the dialogue with Dr. Zhou of Yingshan County Medical Security Bureau, Nanchong City, Sichuan Province, China, we learned a lot, including the largest proportion of drugs reimbursement, the mechanism of new drugs into the national medical insurance, and the determinants of drug inclusion in medical insurance. Dr. Zhou highlighted several important factors that determine the inclusion of new drugs in medical insurance, such as price, efficacy and production cost, which gave us an in-depth understanding of the demand and coverage of new drugs, especially polypeptide drugs, from the government and the national level.
At the same time, Dr. Zhou also said that the difficult problem of the China Medical Insurance Bureau is how to solve the contradiction between the total amount of national medical insurance fund and the acceptance of patients, and precisely our project can provide a cheaper and efficient treatment through long-term drug administration, regular drug administration and safe drug administration, which can not only greatly reduce the burden of patients, but also reduce the burden of the national medical security system. Finally, Dr. Zhou affirmed our project and had high hopes for our project.
Figure 10. Communication with Director Zhou in the office
Chengdu Institute of Biological Products Co., Ltd. is a wholly-owned subsidiary of China Biotechnology Co., LTD., a Fortune 500 enterprise managed by the State-owned Assets Supervision and Administration Commission of the State Council and the largest pharmaceutical industry group in China. The company has long been committed to the research of medical microbiology, immunology and genetic engineering, research and development and production of various biological products for prevention and treatment, diagnostic products, gene recombinant drugs [5]. Since our project is closely related to biopharmaceuticals, we would like to have a general understanding of the production process of biological products through a visit. The greatest significance of the visit was to recognize the difficulty of pharmaceutical production and the importance of the pharmaceutical process to the production of quality drugs. In addition, we also asked Yan some knowledge about the safety of our project, which provided ideas for our Safety. At the same time, we know that the confidentiality of key technologies is very important, so we cannot know and will not ask anything about the technology.
Figure 11. Communication with Researcher Yan
Since one of the drugs we selected for delivery is for the treatment of diabetic patients and diabetes is also a very common chronic disease, we interviewed a diabetic patient who has been using insulin injection for a long time online, hoping to understand his feelings about long-term insulin injection and his thoughts and suggestions on our project. In the communication, he mentioned that he had been using insulin therapy for many years and had to inject insulin every day. He thought it was a painful process and needed to overcome the pain. But it has to be done, otherwise the blood sugar will rise and it will be very uncomfortable. We are sorry that he needs insulin injections every day. In the communication with him, we realized the importance of painless or even autonomous drug administration, and realized that our project has great improvement significance in this aspect. He was very pleased with our project, and also greatly affirmed our project. He said that if our project can finally be realized, it will be a great help to beneficiaries like them. (The patient has authorized our team to use the photo)
Figure 12. Online conversation with a diabetic patient
Images involving portraits of people are published with the consent of the subject.
1. Bass, J.; Fenwick, J.; Sidebotham, M. Development of a Model of Holistic Reflection to facilitate transformative learning in student midwives. Women Birth 2017, 30, 227-235, doi:10.1016/j.wombi.2017.02.010.
2. Cui, Y.; Pei, T.-T.; Liang, X.; Li, H.; Zheng, H.-Y.; Dong, T. Heterologous Assembly of the Type VI Secretion System Empowers Laboratory Escherichia coli with Antimicrobial and Cell Penetration Capabilities. Appl Environ Microbiol 2022, 88, e0130522, doi:10.1128/aem.01305-22.
3. Rosete, B.E.; Wendel, D.; Horslen, S.P. Teduglutide for pediatric short bowel syndrome patients. Expert Rev Gastroenterol Hepatol 2021, 15, 727-733, doi:10.1080/17474124.2021.1913052.
4. Retrieved from https://www.gov.cn/zhengce/content/2021-09/29/content_5639967.htm
5. Retrieved from https://aiqicha.baidu.com/company_detail_66132460823323