Integrated human practices
Silver Medal requirement of 🔗Human Practices is Accepted! Check our 🔗Awards page for details!
We innovatively used the "WHW" (What, How, Will) research model to design the BUCT-China team's 2023 iGEM human practice section. This allowed the project conception to stem from reality, the project advancement to deeply interact with reality, and constant iteration to be achieved through society's feedback on project results, thus forming a closed loop.
Our project became more comprehensive and constantly in-depth, successfully achieving the preliminary construction of a universal detection new platform, facilitating precision medicine in the real world.
We started from the problem of unclear pathogen detection among team members around us, and further considered whether this problem was worth exploring. First, through in-depth communication with doctors and questionnaires, we obtained social feedback, identified potential stakeholders, and then through in-depth interviews and exchanges with people from all walks of life, we determined what kind of meaningful project we wanted to complete, achieving "What", that is, building a universal detection new platform.
Immediately afterwards, through communication with clinical laboratory doctors and professors, we determined how we could achieve our goal, that is, designing molecular probes through Bst polymerase-mediated chain displacement reaction. And after completing the identification of bacteria and viruses in Engineering Cycle 1.0, we communicated with doctors to complete the identification of lung adenocarcinoma in Engineering Cycle 2.0, further verifying the feasibility of building this versatile platform. Throughout the entire experimental process, we were in constant communication with doctors and professors, exploring efficient technical means to achieve the project purpose, realizing "How".
Finally, in "Will", we constantly reflected on the social issues discovered during the exploration process, carried out extensive educational activities, spread the concept of precision diagnosis projects, and assumed our social responsibilities. At the same time, we extensively interviewed stakeholders in society about their evaluations of our results, and actively provided feedback to achieve project iteration, thereby optimizing old systems, discovering new problems, and exploring new solutions to problems.
By achieving a "closed loop" through "WHW", our project becomes better and better, and also provides research ideas for other teams to explore new issues.
How's BUCT-China good for the world?
Throughout the process, we paid special attention to the impact of our technology on society. We hope that under the premise of safety and no social ethical issues, it can efficiently achieve precise diagnosis to promote fair medical resources, and achieve more accurate, efficient, safe and low-cost diagnosis. At the same time, we also hope to provide new ideas for the research and development of diagnostic technologies for other research teams through new molecular computing R&D ideas.
Therefore, we undertook extensive research, conducting in-depth interviews with different groups at each stage. We identified research directions from the public's demands and continuously optimized them, devoting ourselves to building an precise diagnosis platform ("Description"), realizing efficient diagnosis for the benefit of human society ("Implementation").
In this process, we also paid attention to the safety issues of technology in the real world. Our entire project workflow, from input to output, was conducted within an acellular system . It did not involve living individuals and thus posed no biosafety risks ("Safety").
We also hope that our thinking can take creation of knowledge and blaze a new trail for other diagnostic technology researchers ("Contribution").
At the same time, we also hope the dissemination of health concept will be wider, raising more people's awareness of the significance of precision diagnosis to safeguard everyone's health ("Education").
"Extensive research"Extensive research allows us to understand the public's demands more quickly and clearly, and adopt more targeted human practice activities to better promote the project
"In-depth interviews "Through in-depth interviews, we can better understand the significance of our project to stakeholders, and how to better optimize the project through feedback
"Precise diagnosis platform"We are committed to building a precision diagnostic platform to better solve the problems of real-world diagnosis methods
"Efficient diagnosis "We hope to ensure human health through efficient diagnosis, so that our project can benefit more people
"Safety"we also paid attention to the safety issues of technology in the real world. Our entire project workflow, from input to output, was conducted within an acellular system . It did not involve living individuals and thus posed no biosafety risks
"Creation of knowledge "We hope that our new solution ideas will inspire other teams to develop diagnostic techniques and enable creation of knowledge
"Dissemination of health concept"we also hope the dissemination of health concept will be wider, raising more people's awareness of the significance of precision diagnosis to safeguard everyone's health
WHAT are we going to do-Hear from the community
Universal precision diagnosis platform
Brainstorming
Unclear pathogen identification affects the diagnosis and treatment of patients
On March 5, 2023, the World Health Organization (WHO) declared that the COVID-19 pandemic was no longer a "public health emergency". This declaration marked a key step in ending the global COVID-19 pandemic and formally entering the post-pandemic era.
However, at the same time, mainland China still faces the threat of novel coronaviruses and influenza A viruses, which is an unavoidable reality for our team members. At the beginning of the project, team members frequently experienced colds and fevers. Due to the impact of the epidemic on people in the past three years, we often subconsciously assumed that our colds came from the novel coronavirus. So, most team members chose to self-isolate and take antiviral drugs. However, strangely, some team members' symptoms did not alleviate until they were diagnosed at the hospital and realized that they had bacterial colds rather than viral colds.
We realized that this may not be an isolated case. Misdiagnosis due to various reasons may be delaying patients from obtaining precise diagnosis and treatment. The battle between humans and epidemics has never stopped for thousands of years, from the bubonic plague that swept across the European continent a thousand years ago, to smallpox that still plagued lives a hundred years ago, to the recent COVID-19 pandemic that has claimed millions of lives around the world; from the common colds and seasonal flu that affect us from time to time, to the pathogens that challenge human health all the time... How to confirm whether it is a viral infection or a bacterial infection that causes physical discomfort, in order to prescribe the right medicine and treat efficiently, is extremely important.
Due to the similar symptoms of bacterial and viral infections, the harsh application conditions of existing detection technologies, and the uneven distribution of medical resources, clinical misdiagnosis of viral and bacterial infections is common. This not only delays patients from obtaining accurate diagnosis and treatment, but also exacerbates the threat posed by drug-resistant pathogens due to the misuse of antibiotics.
In addition, it also aroused BUCT-China's thinking: do other diseases also have a high misdiagnosis rate? How important is accurate diagnosis?
On June 6, 2020, The Lancet published a study titled "Quality of primary health care in China: challenges and recommendations". It pointed out that only 26% of primary care doctors made correct diagnoses for anonymous standardized patients. 1 At the same time, the overuse of antibiotics is very common in China's primary medical institutions, far exceeding the standards recommended by the World Health Organization. On October 18, 2011, the Ministry of Health of China stated that the usage rate of antibiotics for patients in China reached 70%, but less than 20% really needed them. 2
This shows that due to insufficient primary medical facilities and lagging medical diagnostic methods, China has difficulty giving patients correct diagnoses and treatment recommendations, which also indirectly leads to problems such as antibiotic abuse. Many diseases have similar symptoms, and current medical means still cannot make completely accurate judgments. The resulting misdiagnosis and missed diagnosis problems, and even the increasingly serious problem of antibiotic abuse, are not only the plight faced by China, but also issues that the whole world should pay attention to (a report released by the World Health Organization in 2019 pointed out that inappropriate prescription rates and overuse of antibiotics led to resistance, causing a global health emergency, killing at least 700,000 people each year 3).
Therefore, developing new detection methods to deal with misdiagnosis and missed diagnosis, and help curb antibiotics, is especially important for fighting malignant diseases such as cancer.
This has also attracted great attention in China. The "14th Five-Year Plan for the Development of the Bioeconomy" points out: improve the ability to diagnose diseases. Promote the integration and innovation of biotechnology with advanced technologies such as precision machinery, new materials, and additive manufacturing, vigorously develop advanced diagnostic technologies and products such as molecular diagnostics, chemiluminescence immunoassays, and point-of-care testing, develop high-end medical imaging and other diagnostic equipment, and promote the development of intelligent, miniaturized, rapid, accurate, and multi-functional integrated equipment. China's National Precision Medicine Major Project has been launched, and it is expected to invest 60 billion yuan in basic research before 2030.
Figure： Nation development and reform commission issued the "14th Five-Year Plan for the Development of the Bioeconomy"
BUCT-China is also willing to assume social responsibility and make our contribution to achieving accurate diagnosis. Therefore, we started this year's iGEM journey, starting from the problems of our friends and family, committed to studying how to quickly and easily determine infection types to guide subsequent drug treatment, while better coping with drug resistance. At the same time consider efficient and accurate diagnosis for other diseases, try to find new technologies for accurate diagnosis!
Interviewing a Doctor
Understand the significance of achieving precise diagnosis
Liu Jinsheng
Professor, Beijing University of Chinese Medicine; Chief Physician
Compared with modern medicine's reliance on various instruments to make diagnoses through image analysis, biochemical analysis, etc., traditional Chinese medicine has a unique diagnostic approach. We were fortunate to invite Professor Liu Jinsheng from Beijing University of Chinese Medicine for an interview to understand the current medical situation. Professor Liu has worked clinically for many years as a TCM doctor with rich diagnosis and treatment experience. He has also served as the director of the Scientific Research Department of Beijing University of Chinese Medicine, familiar with various modern medical diagnosis and treatment methods. He specializes in the diagnosis and treatment of respiratory diseases and has helped tens of thousands of patients through the combination of traditional Chinese medicine and Western medicine. We asked him about the current development status of clinical diagnostic techniques.
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This also reflects a problem that in many cases, if we can intervene in a timely manner when the disease has very little impact on the human body, we can often achieve better therapeutic effects. And for many diseases, it is often too late to intervene when they have produced significant effects on the human body. Therefore, compared with treating after onset, early accurate diagnosis is more important.
Developed to modern times, TCM has also achieved better integration with modern science. Through modern detection technology, we can also make better judgments. We also look forward to better modern diagnostic technologies to benefit more patients.
In addition, he pointed out that although modern science and technology are very advanced now, and the diagnosis and treatment of diseases are much more efficient than before, due to the complexity of the causes of various diseases, we still cannot achieve accurate diagnosis. Professor Liu encouraged us to have the scientific spirit of thinking triggered by phenomena in daily life.
He also aroused our thinking: How many people in daily life have experiences similar to our team members where they have difficulty judging the cause of their illness? How important is accurate diagnosis?
Questionnaire survey
Understand social demands and identify potential stakeholders through analysis
Through interviews with doctors, we recognized the importance of accurate diagnosis for disease prevention and treatment. " We also wanted to investigate the impact of precision diagnosis on the public in real life. "So, starting from the topic of brainstorming, the BUCT-China team conducted a public survey on precision diagnosis, hoping to further explore the value of the project and guide the research direction of the BUCT-China team's iGEM journey this year, and provide new ideas for the development of human practice activities!
The BUCT-China team began to take extensive surveys in the hope of understanding the social status quo. Questionnaire 1.0（Click to view the Survey and detailed analysis）
Interviewing stakeholders
Define the necessity and direction of the project
1. Child care physician
Huang Rui
Preschool doctor
Children have weaker resistance and often suffer from colds and fevers. At the same time, it is difficult for young children to accurately express their symptoms, which increases the difficulty of diagnosis. Therefore, more efficient and accurate detection methods will not only bring convenience to young patients, but also provide technical assistance for preschool doctors to make accurate diagnoses for patients. To this end, we were fortunate to interview Huang Rui, a doctor from Luoyang Wanda Kindergarten, to understand the needs of different stakeholders for new diagnostic technologies. In addition, Dr. Huang volunteered in remote areas to provide free medical treatment for local residents and shared the medical difficulties in underdeveloped areas with the BUCT-China team.
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Dr. Huang also talked about her experience of volunteering in poor areas. She told us that people in poor areas often have poor awareness of seeking medical treatment and do not go to hospitals for fear of high medical expenses, which eventually leads to worsening conditions that are difficult to cure. In addition, the low level of medical care in poor areas cannot provide high-quality medical services to patients, which also forces patients to leave their villages and travel long distances to cities for medical treatment. The lack of awareness of seeking medical treatment and the backwardness of medical standards restrict doctors' treatment of patients. If there is a simpler and cheaper detection method that allows patients in poor areas to obtain accurate diagnoses locally, it will greatly promote the development of rural medicine.
Communicating with Dr. Huang prompted the BUCT-China team to pay more attention to potential stakeholders -- children. We also worked with Dr. Huang to organize popular science lectures and adopted various interesting ways to guide children to develop awareness of personal hygiene (see Education for details). At the same time, we also realized that there are medical difficulties in poor mountainous areas. This also provided ideas for the direction of our technology development. Can accurate diagnosis of various diseases be achieved? Can diagnosis with lower costs and greater convenience be achieved? These are the key directions that BUCT-China will focus on next!
2. Doctor
Li Xu
Chief Physician, China-Japan Friendship Hospital
'What difficulties are there in clinical diagnosis that are waiting for new technologies to help solve?' Is it low accuracy? Is it slow detection speed? Or is the detection process too cumbersome? These are all contents that BUCT-China wanted to understand in order to determine the implementation direction of the project. In order to understand the needs of precision diagnosis and treatment in clinical settings, we were fortunate to invite Dr. Li Xu from China-Japan Friendship Hospital. Dr. Xu has rich clinical experience and is familiar with front-line diagnostic techniques. He has a profound understanding of the current medical situation and provided valuable ideas for the BUCT-China team's 2023 iGEM research.
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As a hepatobiliary surgeon, Dr. Xu also introduced the disadvantages of current diagnostic technologies. Traditional pathological biopsies are highly invasive detection methods with high health risks for patients, and they are also not repeatable. Whether it is the early, middle or late stages when cancer is suspected, there is no way to take multiple punctures to observe the changes and development of the disease. Therefore, in terms of repeatability, or long-term observability (being able to take samples regularly for comparative observation), Dr . Xu hopes that we can make some breakthroughs.
Finally, Dr. Xu emphasized that in addition to the huge clinical demand for cancer diagnosis, the clinical demand for specific identification of complex infectious pathogens is also huge. It is still very difficult to specifically identify which type of pathogen or which pathogen, so Dr. Xu suggested that we can try to explore a new technology through new ideas for accurate diagnosis, and try to use the problem discovered by our project's starting point, unclear pathogen identification, to verify the feasibility of our technology, and constantly expand the scope of application of the technology to repeatedly verify the versatility of the project!
In addition, as a clinical doctor, Dr. Xu can see more needs of clinical patients and medical systems, and is more concerned with practical operations, so he thinks more about how to solve practical problems. Therefore, in terms of project research, he suggested that we can observe and collect information from multiple perspectives, listen to the voices of multiple professions and stakeholders, pay close attention to the actual situations and ideas of different levels and groups of people.
Through communicating with Dr. Xu, BUCT-China is determined to build a versatile precision diagnostic new platform to achieve more accurate, faster, more convenient and less painful diagnosis through a cell-free in vitro system!
3. Professor
Guofeng Li
Associate Professor, Beijing University of Chemical Technology
After we had the preliminary idea of building a 'versatile' precision diagnostic new platform, we first communicated with the team's PI to understand the assessment of the necessity of this project from the perspective of biological technology, in order to guide the project's progress. Professor Li Guofeng has long been devoted to the fields of antibacterial and anti-tumor research. He is also very familiar with the early diagnosis in related diagnosis and treatment processes. Through the conversation with Professor Li, we learned that building a versatile diagnostic platform has a good promotive effect on the in-depth practical application of life technologies. This is a challenge, and also an opportunity for humans to discover better ways to combat pathogens!
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Professor Li's research focuses on the antibacterial field. He introduced that humans have long been plagued by various pathogens, whether it is the Black Death caused by Yersinia pestis, the smallpox virus, or the recent COVID-19 pandemic, they have seriously endangered human health. The treatment of these diseases also faces great difficulties, the disease process is painful, and the recovery effect is poor. If there are more accurate means to achieve accurate diagnosis at an early stage, it will undoubtedly greatly help subsequent precision treatment and improve the cure rate.
At the same time, he pointed out that the development of life sciences ultimately is to benefit human society. How to make a new technology benefit this society more is an issue that every biotechnology researcher needs to think carefully about. If BUCT-China can build a new diagnostic platform through cutting-edge life science and technology, it will also provide new ideas for technology transformation for other researchers.
Through communicating with Professor Guofeng Li, BUCT-China became more determined to build a versatile precision diagnostic new platform. BUCT-China will also seize this opportunity to use cutting-edge life science and technology to explore new ideas for precision diagnosis and treatment and benefit the real society.
Build a universal precision diagnosis platform
BUCT-China's 2023 iGEM journey stems from the brainstorming of team members facing unclear judgments of viral and bacterial infections leading to delayed treatment. The interview with Dr. Jinsheng Liu made us realize the importance of accurate diagnosis in clinics
Through the analysis of the questionnaire, we deeply realized the necessity of our desired precise diagnosis project goal for society
Through communicating with Dr. Rui Huang, we further understood the demands of grassroots potential stakeholders for precision diagnosis
Through communicating with Dr.Li Xu and Professor Guofeng Li, we once again profoundly recognized the importance of achieving precision diagnosis and treatment for clinical and scientific progress, and finally clarified what we want "WHAT", that is, building a versatile precision diagnostic new platform.
BUCT-China is committed to building a versatile precision diagnostic platform in 2023 iGEM with the technical development direction of achieving more accurate, more convenient, and lower cost, in order to achieve accurate diagnosis and help more patients obtain accurate treatment!
HOW do we achieve our goals-Interact with the community
DNA molecular probes based on polymerase-mediated strand displacement reactions
Interview the diagnostic technology researcher
Seek feasible technical route
Yahui Lin
Assistant Chief Physician, Deputy Researcher, Peking Union Medical College Hospital
After clarifying that we need to build a 'universal' precision diagnosis new platform, we first contacted a senior diagnostic technology researcher for an interview, trying to initially determine the most feasible and innovative breakthrough plan, and find a technology that is more advantageous in terms of cost, detection efficiency, detection sensitivity, and detection accuracy. In order to finalize the innovative detection method used by the 'universal' precision diagnosis new platform, we had in-depth discussions and exchanges with Professor Yahui Lin. Professor Yahui Lin's main research direction is laboratory detection and clinical application of cardiovascular disease markers, as well as POCT quality management. He has a long history of research experience and rich research experience in the field of clinical detection. In the early stage of the project's conceptual design, he provided clearer exploration directions and valuable suggestions for the BUCT-China's 2023 iGEM research project.
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Therefore, Professor Lin suggested that "more attention can be paid to the microscopic biological small molecule level in the future, trying to tap into emerging cutting-edge precision diagnosis techniques such as molecular diagnostic technology, and look for markers with both high sensitivity and accuracy." Of course, no matter which diagnostic technology is developed, the accuracy of the test results is the first priority. If the project succeeds, it will bring a major breakthrough to the field of medical diagnosis and contribute innovative solutions, which can further promote its application in the early screening and disease typing of diseases related to classical genetics and epigenetics, making treatment regimens and medication more sophisticated and "gradually forming a closed-loop of precision medicine".
In addition, Professor Lin also mentioned that although some molecular diagnostic technologies are already being used in the field of clinical detection, such as MRD and NGS, there are still some challenges that need to be improved, such as the difficulty in detecting homogenized results from different instruments. Not only that, but the application scope of these molecular diagnostic technologies is also very narrow, limited to only a few cancers that have been fully characterized.
Professor Lin believed that "we might be able to leverage cutting-edge AI and big data algorithms to help us find markers that can perform accurate detection, or introduce logic circuits at this biological small molecule level to achieve some direct analysis and calculation of markers." This way, our project can just fill in the previous lack of research on the crossover and integration of cutting-edge computer technologies such as bioinformatics and artificial intelligence algorithms, and will also have very strong competitiveness and broad practical application prospects.
Through communicating with Professor Lin, BUCT-China decided to use "machine learning and molecular computing diagnostic technology" as the key core technology and innovation highlight for building a "universal" precision diagnosis new platform, in order to achieve more sensitive and accurate detection and diagnosis in early disease screening. At the same time, inspired by the discussion with Professor Lin on precision medicine, BUCT-China began to conduct a series of popular science on precision medicine for the general public on social media and offline people of all ages (click on "Education" for details).
Molecular computational diagnostic technique
After confirming the innovation highlight of using ""machine learning and molecular computing diagnostic technology"" to build a ""universal" precision diagnosis new platform", we hope to further communicate in depth with experts and professors who have relevant research experience in bioinformatics. " We expect to use bioinformatics analysis combined with machine learning to help us find brand new biomarkers, deeply study the experimental design plan for the molecular computing module, and seek ways for our original ideas to be implemented in practical operations."
Interview PI
Ask about experimental design
Dry Lab PI
Su Xin
Visiting Professor, Beijing University of Chemical Technology
Professor Xin Su's main research interests are developing advanced diagnosis and treatment methods based on DNA nanotechnology and advanced synthetic biology. As the Primary PI of our team, he provided full support and careful guidance for the modeling and wet lab parts of the BUCT-China's 2023 iGEM research project.
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In addition, we also shared with Professor Su some related ideas about the molecular computing module in the experimental design ideas. First, the logic circuits of molecular computing can emulate the computing structure and patterns of human neural networks, rather than being limited to traditional NAND gate circuit designs; Second, after consulting relevant cutting-edge research literature abroad, we found that Bst polymerase has strong strand displacement ability to catalyze DNA isothermal amplification reactions, so Bst polymerase will be the best tool for molecular computing; Third, if we want to further simplify and strengthen the functions of the molecular computing system we have built," we need to consider not only unified weight chains, but also ways to achieve more complex molecular computing."
These creative ideas and experimental ideas impressed Professor Su. He believed we could continue to explore deeply in this direction, and then it would be better to directly use the large fragment form of Bst polymerase in the molecular computing process, which would gradually enable our ideas to be put into practice. At the same time, he also introduced us to a new idea of implementing multi-level cascaded molecular multiplication operations, affirming our hard work and the scientific research value and social impact created from multiple perspectives. His advice also provided ideas for "optimizing our experiments."
Wet Lab PI
Zhao Yang
Associate Professor, Beijing University of Chemical Technology
Professor Zhao Yang's main research field is precision treatment of tumors. As the Primary PI of our team, he gave great support and careful guidance to the wet lab part of the BUCT-China team's 2023 iGEM research project.
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Polymerase-enabled Molecular Computing
After further in-depth discussions, close communication with the PIs, repeated debating, and collecting literature and suggestions from professors and experts, "we finally decided that the "universal" precision diagnosis new platform we want to build should apply Polymerase-enabled Molecular Computing diagnostic technology." We start from the dynamic changes of biological small molecules during the disease process at the microscopic level, detect molecules directly related to the essence of the disease, and use this to "design specific experimental schemes for wet lab experiments while simultaneously developing the idea of iterating and upgrading Engineering Cycle 1.0 and Engineering Cycle 2.0," hoping to achieve the expected results of accurate prediction and accurate judgment. It is worth mentioning that in this process, "we have also actively interacted with the iGEM Community around us at different levels," participating in the 10th CCiC Conference, the 2023 Beijing Regional iGEMer Communication Meeting organized by BNU-China, and the 2023 Entrepreneurship Seminar planned by Squirrel-CHN. We show our research results and innovative ideas at the current stage to other iGEMers, exchange excellent experiences with each other, and provide practical helpful suggestions, making us increasingly confident and enthusiastic about this year's project, while also further expanding BUCT-China's influence.（click on "Communication" for details）
Interview Doctor
Determine the direction of the next engineering cycle
Huijie Wang
Deputy Chief Physician, Department of Medical Oncology, Fudan University Shanghai Cancer Center
After completing the identification of bacterial and viral infections in Engineering Cycle 1.0, we further conducted in-depth communication with clinical cancer research expert doctors to improve the learning part of Engineering Cycle 1.0. We hope to obtain feedback information from different perspectives to guide the development direction of our Engineering Cycle 2.0. Chief Physician Huijie Wang is familiar with the clinical routines for treating common malignant tumors. He is currently focusing on internal medicine treatment of thoracic tumors and soft tissue tumors. Chief Physician Wang answered questions and provided valuable suggestions for the learning phase of Engineering Cycle 1.0 and the design phase of Engineering Cycle 2.0 of the BUCT-China's 2023 iGEM research project, especially providing more practical guidance on the application field of our technology.
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He then put forward constructive opinions on the direction and ideas for us to continue in-depth research in the next engineering cycle.
Chief Physician Wang pointed out that the identification of bacterial and viral infections that we have completed in Engineering Cycle 1.0 is necessary to continue in-depth iterative exploration, because liquid biopsy technology is a hot spot with huge demand in the field of early tumor diagnosis. However, there is currently no very mature and improved technology available for clinical application. Cancer types are numerous, and the causes of cancer are very complex. In the discussion during the middle stage of the project, the team members also considered focusing Engineering Cycle 2.0 on researching one type of cancer, but there were still more confusions about the selection of suitable cancer types and related research.
Regarding this, Chief Physician Wang pointed out that "we can first focus on designing experimental schemes for one type of cancer". He then provided us with "two ideas for selecting cancer types":
First, find "a disease with a large number of cases and it is easy to obtain patient samples", because such diseases use classical pathological examinations for diagnosis very maturely, with sufficient data for comparative analysis and verification
Second, find "a cancer that currently has some difficulties in diagnosis and screening", such as difficulty in distinguishing whether it is benign lung cancer. In this case, if the experimental results can significantly improve and enhance the current detection technology, it would be equivalent to providing a new solution to address a major pain point in the diagnosis of these diseases.
Through communicating with Chief Physician Wang, BUCT-China confirmed the entry point for the iterative upgrade of Engineering Cycle 2.0 and the basic idea of experimental design, improved the feedback loop of the learning part of Engineering Cycle 1.0, and gained a deeper understanding of cancer detection related knowledge and technology. We glimpsed the technical feasibility and broad prospect of the "universal" precision diagnosis new platform constructed by "molecular computing diagnostic technology based on Bst polymerase" being applied to cancer detection.
Yi Cai
Deputy Chief Physician, Deputy Professor, Department of Medical Oncology, Cancer Center of Chinese PLA General Hospital
After confirming that Engineering Cycle 2.0 would focus on cancer identification research, we further conducted in-depth communication with senior chief oncologists to obtain brand new feedback information to stimulate our innovative technology to successfully iterate to Engineering Cycle 2.0. Chief Physician Yi Cai specializes in chemotherapy, targeted therapy, and immunotherapy for lung cancer and targeted therapy and immunotherapy for liver cancer. He is familiar with diagnosis and treatment methods for common cancers such as breast cancer, esophageal cancer, gastric cancer, colorectal cancer, cholangiocarcinoma, pancreatic cancer, renal cancer, and bladder cancer. He has rich experience in the comprehensive treatment of malignant tumors with complicated underlying internal medicine conditions. He provided relatively clear research ideas and valuable suggestions for the design and construction phase of Engineering Cycle 2.0 of the BUCT-China 's 2023 iGEM research project.
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About two years ago, due to the impact of COVID-19 infection, some patients who came to the hospital for a lung CT scan were found to have pulmonary nodules. Pulmonary nodules and lung cancer are two completely different disease concepts. Most pulmonary nodules are likely to be benign, but once patients find they have pulmonary nodules, they become very nervous, worrying whether it will develop into lung cancer. So at that time, Dr. Cai did a lot of exploration on how to diagnose pulmonary nodules as early lung cancer. He also discovered some biomarkers, and then wanted to combine imaging data and artificial intelligence analysis, but ultimately did not get an ideal early diagnosis plan.
"Regarding the entry point for the iterative design of Engineering Cycle 2.0 of our project technology, Dr. Cai pointed out that lung cancer, the world's largest cancer, is an excellent choice." Lung cancer has the largest clinical demand. It can even be further accurately defined as lung adenocarcinoma combined with early diagnosis of pulmonary nodules (judging whether it will develop into non-small cell lung cancer). Then go on to generalize, upgrade and transform it for detecting other types of tumors.
In addition, Dr. Cai pointed out that "our project technology can also try to explore and implement relevant concept verification in the field of post-treatment recurrence monitoring of tumors", supplementing and expanding the application scenarios of our project. This is because studying the post-treatment recurrence of a specific cancer is more specific than its early screening. It is a smaller issue and a problem in which data indicator changes can be observed well.
Dr. Cai emphasized that "in-depth exploration and verification of post-treatment recurrence monitoring of tumors will be more conducive to improving the sensitivity and accuracy of our technology. And it is relatively easy to come up with innovative solutions for newly discovered problems." Moreover, from the perspective of verifying clinical actual samples, it is also easier to obtain more samples that have been diagnosed with cancer and are undergoing post-treatment recurrence detection, which facilitates our pathological verification and comparison with benign or negative data. The experimental results can also be compared with the accuracy of existing post-treatment monitoring methods to highlight the advantages and innovation of our technology.
Through communicating with Chief Physician Cai, BUCT-China recognized that the iterative upgrade of Engineering Cycle 2.0 can start from the detection of non-small cell lung cancer for experimental design, and the "universal" precision diagnosis new platform constructed by "Polymerase-enabled Molecular Computing diagnostic technology" can be applied to post-treatment recurrence monitoring of tumors. We learned the method of experimental model verification, and experienced the profound impact and practical application value of our project.
Verify feasibility
To further verify the technical feasibility of building a "universal" precise diagnosis platform
BUCT-China's 2023 iGEM journey is steadily moving forward. In the early stage of the project, through communicating with Professor Yahui Lin, we determined the key core technology and innovation highlight of this project; then under the strong support and careful guidance of the team PIs, we completed the design, construction and verification of Engineering Cycle 1.0 and 2.0; of course, the transformation of the research ideas in Engineering Cycle 2.0 also stems from our active in-depth discussions with Chief Physician Huijie Wang and Chief Physician Yi Cai. " Our experimental ideas were inspired and the development path of subsequent engineering cycles became clearer. The links between the various parts are more closely connected."
After undergoing severe tests, BUCT-China knows "HOW" to " continue the spiral rise of our technology" : in the bioinformatics modeling section, we independently completed the programming and operation of machine learning; in the experimental design optimization of the wet lab section, we innovatively used LATE-PCR to amplify target signals, repeatedly improved the design of different primers combined with LATE-PCR for different targets, and boldly tried using the large fragment of Bst polymerase for chain replacement reactions, which unexpectedly facilitated our independent expression of this protein fragment; after completing the two engineering cycles, we also came up with the innovative idea of introducing microfluidic chips to assist detection to further improve the sensitivity of the " Polymerase-enabled Molecular Computing diagnostic technology "......
Of course, in the process of solving problems, actively embracing challenges, continuously breaking through self-limitations, and long-term human practices interacting with society, the profound social benefits and global impacts behind our project implemented this year have also been deepened - accelerating the operational efficiency of the medical cycle, promoting the integration and development of bioindustry and biotechnology, tapping the potential of the biomedical industry......(click"Implementation"to know more)
Next, BUCT-China will bring the initially embryonic " Polymerase-enabled Molecular Computing diagnostic technology " into real life, "taking root in all levels and fields of society, and carry out extensive and profound dual-line exploration of humanities and science and technology. Seek different levels of feedback from interactions with all sectors of society to help us make further iterative upgrades in the future." BUCT-China hopes to provide a solution featuring our own characteristics for the technological innovation in the field of precision medical diagnosis in the future world, acting as a bridge to benefit society, catalyzing the infinite possibilities of molecular diagnostic technology, and highlighting BUCT-China's social responsibility and commitment.
What will we do-Close the loop
> make our technology benefit society and evolveStakeholder feedback
Evaluation of project results for social feedback
After a series of progress in Engineering Cycle 2.0, we interviewed some professional doctors, university professors, and bioinformatics diagnostics practitioners in depth again, hoping to obtain a three-dimensional evaluation of the results of Engineering Cycle 2.0 from relevant stakeholders and seek further development and optimization of our team's project.
Yi Cai
Deputy Chief Physician, Deputy Professor, Department of Medical Oncology, Cancer Center of Chinese PLA General Hospital
In the early stage, we had discussed with Chief Physician Cai Yi about the innovative iteration direction of Engineering Cycle 2.0. After completing the preliminary construction of the versatile diagnostic platform, we revisited Chief Physician Cai to discuss the latest progress of the team's Engineering Cycle 2.0, hoping to get advice and guidance from front-line professionals in the counterpart profession.
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He also added that this technology also combines a very popular cutting-edge field - artificial intelligence, big data and machine learning. Developing and exploring in depth in this direction through cross-fusion is also a very valuable and promising endeavor.
At the same time, Chief Physician Cai also pointed out that the number of non-small cell lung cancer target genes involved in our current Engineering Cycle 2.0 is still too small to be truly mature, so he hopes that our engineering cycle can continue to improve, " screen more target genes, collect data, and ensure reliable diagnosis in the technical theory field first."
In addition, Chief Physician Cai pointed out that in addition to being applied in the field of early precision diagnosis, our precision diagnostic versatile platform can also shine in the field of prognosis monitoring, such as breast cancer tumor recurrence monitoring. "He pointed out that the current demand for post-intervention monitoring and review of various tumors is huge, and also suggested that we can explore non-blood testing directions, such as feces, urine, saliva and other samples. Because such diversified sample detection methods can not only make up for the blind spots of imaging (such as detection of tiny tumors in the colonic mucosa) but also enhance patients' enthusiasm for detection."
Qingsong Yu
Associate Professor, Beijing University of Chemical Technology
In order to obtain an evaluation and advice on our project technology from the perspective of biotechnology, so that we can optimize the technical implementation, we were fortunate to interview Associate Professor Yu Qingsong from Beijing University of Chemical Technology. Professor Yu specializes in the development of new tumor diagnosis and treatment methods. He is very interested in our project results and gave us valuable advice on technical optimization.
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But Professor Qingsong Yu then emphasized that when optimizing technology, we must put accuracy first, which is fundamental and cornerstone. Secondly, he also expressed concerns about whether the technology has strong versatility. Mutations in different diseases under different environments are most likely different. Target abundance and probe sensitivity are by no means fixed data. The detection limit is the biggest restriction on technology implementation. And there is a considerable probability that errors will occur when the signal is cascade amplified. For example, false positives often occur when testing for SARS-CoV-2. Therefore, "he hopes that the number of cycles of cascade amplification can be reduced as much as possible."
Qiang Su
Chief Physician, Department of Oncology, Beijing Friendship Hospital, Capital Medical University
After initially building the 'versatile' precision diagnostic new platform, we hope to further communicate in depth with experts in the field of bioinformatics, obtain objective evaluations, and seek ways for innovative ideas to be implemented in practical operations. Therefore, we were fortunate to invite Chief Physician Qiang Su from the Department of Oncology, Beijing Friendship Hospital, Capital Medical University for an online interview. Chief Physician Qiang Su has been engaged in clinical learning and research for more than 20 years. He specializes in comprehensive treatment (including targeted therapy, immunotherapy, etc.) of malignant solid tumors. He also has relevant cutting-edge research experience in combining bioinformatics and machine learning. He provided objective evaluations and some support, guidance and professional advice for the BUCT-China team.
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Chief Physician Su affirmed again the innovation and application prospects of our technology. He believed that our precision diagnostic technology integrates bioinformatics, artificial intelligence, big data and molecular biology into an interdisciplinary innovative project with excellent starting point and purpose. From the perspective of clinical practice, no matter what disease, the first step is to diagnose and analyze the condition and identify the cause. Therefore, if a new detection technology can be developed to assist current disease diagnosis and highly match clinical needs, it will surely make the medical industry shine. Our project is like opening up a new model in the field of diagnosis. "It performs diagnosis at the molecular level, combines machine learning in the target screening process, and minimally invasively collects patient samples, with distinctive features."
Secondly, he believed that our project has a wide application scope covering multiple fields. "Looking horizontally, it can screen multiple types of tumors; looking vertically, it can be applied to the entire cycle of tumor diseases, including early screening of tumors and continuous monitoring of prognosis." In summary, it can be said to be a project with highly innovative concepts and unique advantages, broad prospects, and ample room for in-depth exploration and optimization.
"Chief Physician Su believed that machine learning has great potential. We may consider selecting other algorithm models to further optimize the current program." Starting from his previous learning and research experience, Chief Physician Su gave us a suggestion: In the process of designing machine learning, a "flowchart" model can be used to establish the framework and assist in inspection. This can clarify the complete process of machine learning more clearly, and it is also convenient for us to form a unique idea of applying machine learning, and then we can apply it to wider fields.He exclaimed that if our results can be implemented, such a new detection platform will be of great help to clinical diagnosis. "So he solemnly reminded us to pay attention to verifying target sensitivity and specificity."
"Through the evaluation of our project by stakeholders, we have a clearer understanding of our results. "This not only inspired the BUCT-China team to continue to optimize our project, but the valuable suggestions provided by the interviewees also gave us "new ideas on how to further tap the potential value of the project", how to make the project better benefit society, and how to further optimize our project.
Technology implementation
Make technology better benefit society
Thanks to the highly developed molecular biology and the rapid advancement of technologies such as artificial intelligence and big data screening, biological molecular diagnostics have gradually shown broad application prospects in medicine. The BUCT-China team designed DNA molecular probes that can perform weighted summation calculations through polymerase-mediated chain displacement reactions to form an artificial biochemical neural network circuit. It can perform weighted summation on multidimensional biological marker input signals to output more intuitive low-dimensional judgment results for in vitro diagnosis and disease identification.
In this technology, the innovative use of polymerases to design molecular probes not only reduces errors caused by leakage and improves the accuracy of the system, but also replans the weighting process to reduce the design and manufacturing costs of the weight chains, greatly reducing the complexity of the reaction and enabling molecular diagnosis involving high weight targets.
In the future, this technology may be able to build a versatile precision disease diagnostic platform to achieve a new, more accurate diagnostic method, assist doctors in achieving accurate diagnosis and treatment, and benefit patients around the world. BUCT-China has also deeply considered how this technology can actually benefit human society and the various problems that need to be solved. (click "Implementation" to know more details)
Promotion and popularization
Promoting the concept of precision medicine
If a technology cannot be recognized by the vast majority of people, it will be difficult to sustain healthy development and establish a virtuous cycle. Therefore, our team has carried out a series of educational activities and cooperative attempts to expand our influence and spread our project concept - precision diagnosis to society.
We first tried to find cooperative partners among the participating iGEM teams. So we successively established close cooperative relationships with CJUH-JLU-China and BUCT these two teams. Through Tencent Meeting, WeChat and other media, we shared the wonderful projects of each other's teams with CJUH-JLU-China. Offline, we not only participated in the Beijing Regional iGEMer Conference together with BUCT, conducted project introductions and sharing, jointly interviewed some experts and scholars, but also jointly held a synthetic biology lecture at Beijing University of Chemical Technology, benefiting each other greatly.
Afterwards, "we also carried out a series of online and offline educational activities for non-professionals at the same time." This includes relying on popular social media to publish numerous videos and popularize relevant synthetic biology knowledge; establishing a social practice team to visit various personnel-intensive places in Chengde, Hebei to promote precision diagnosis; organizing synthetic biology debates at schools and cooperating with local educational institutions to conduct popular science activities on disease diagnosis in an entertaining way for children (click on "Education." and "Collaborations" for details).
Technology development
close the loop to guide the technology to continuously optimize iterations
How to continuously optimize and iterate technology to better serve human society is the focus of BUCT-China's thinking. We start from the pain points in daily life around us and conduct extensive research to find R&D inspiration. From Engineering Cycle 1.0 distinguishing between bacterial and viral infections to Engineering Cycle 2.0 early diagnosis of non-small cell lung cancer, to establishing a versatile diagnostic platform in the future and performing accurate diagnosis with high precision and low detection limits in the future, our technology is constantly evolving to better serve human society. Our follow-up work will also maintain contact with experts, the public and other relevant stakeholders, collect feedback and continuously optimize core technologies.
Form a virtuous cycle of technology guiding product development, product application benefiting society, and social feedback promoting technological iteration and upgrading, in order to achieve more convenient, accurate and efficient detection effects.
Conclusion
Our project originated from the problem of unclear pathogen identification that occurred around us. After in-depth research interviews, we found that many diseases are difficult to accurately identify.
So we took a longer-term view and decided to build a new versatile precision diagnostic platform. In the end, through the chain displacement reaction mediated by Bst polymerase, we designed molecular probes to provide new ideas for precision diagnosis. In the process of project exploration, we not only learned about social demands through extensive social surveys, but also maintained close communication with stakeholders to determine how our work is responsible and beneficial to the world. We also communicated with professors and doctors in related fields to efficiently advance project progress.
At the same time, we extensively participated in various social activities, continuously exchanged and collaborated with various organizations, improved public health awareness through popular science activities for different groups, and promoted the value of synthetic biology.
Through in-depth human social practice activities, our vision is to let our stakeholders understand the design of the project and their desires, which can be used to adjust our expectations and guide the specific progress of our project in order to establish a closed loop between each other.
References
1 Xi Li,Harlan M Krumholz,Winnie Yip... & Shengshou Hu.(2020).Quality of primary health care in China: challenges and recommendations. The Lancet(10239). doi:10.1016/S0140-6736(20)30122-7.
2 Xi Li,Harlan M Krumholz,Winnie Yip... & Shengshou Hu.(2020).Quality of primary health care in China: challenges and recommendations. The Lancet(10239). doi:10.1016/S0140-6736(20)30122-7.
3 World Health Organization, (2019) "New report calls for urgent action to avert antimicrobial resistance crisis"