Self-reflection and Overview
From the first time a human pulse beats, it signals the existence of a self-defined human being in the universe, which will resonate with all things in his world for about 3 billion times.
Through the process of nutrition, respiration, movement, excretion, growth, reproduction, and sensitivity, we human beings practice ourselves to interact with the outer world to connect the nature inside our body to the nature outside.
Driven by our genes and original desires, navigated by our values which are formed by the mutual modification of sensibility and rationality, we are constantly practicing what we are perceiving and perceiving what we have practiced; practicing what our predecessors have done and what they have not done; practicing what we are constantly repeating, and what we want to do but have not yet been able to do; practicing to take different values from other’s lives as mirrors to reflect on ourselves, as well as influencing the people surrounding us by our own experiences; and practicing to connect the past and future at this moment of our existence.
Human spends the entire life practicing, at every moment and every second, or we can say: Life itself is a magnificent and mysterious journey of human practice.
Similarly, transitioning from the Human Practice of individuals to the Human Practice of the iGEM team and our project “CavengerX”, preventing us from falling into the metaphysical bias of science, we are relentlessly seeking and coordinating what’s the real demand by the public, society, career from our project in the past, in the future and at present, and then return back to our own demand or goals. This is not only about put the specific technology of our project into practice, but also involves with functioning the theory, intention, and consideration lies behind the technology into the ethical, political or economical framework of the society well, which relies on the two important unique but interactive pathways: integrated Human Practice and Education.
So, this is how we interpreted and stepped from the essence of the words “Human Practice”, and how the grounded logic and philosophy of our Human Practice Part in the 2024 UM-Macau iGEM project is seeded and constructed.
Figure 1.1.1. The first meeting and dissuction of CavengerX HP work.
Topic-level design of HP work
With a focus on problem solving, iterating our projects, and the promotion of our self-reflection, UM-Macau 2024 began by building an overall top-level design (Figure) for our human practice work, taking into account all the possible stakeholder and facilitation considerations available to us. We did this to help us consider how to integrate our work with specific groups and communities from the beginning, to understand how our projects would have specific impacts, and to iterate on CavengerX by gaining a deeper understanding of the needs of future audiences and how our projects would be practiced in the real world in the future.
Figure. 1.2.1. The overall top-level design of our HP work.
--Academia
From an academic point of view, experts and professors who specialise in oncology, biomedicine and bioinformatics have a clear understanding of the field in which our project. They are able to give us guiding advice from their experience and were the most important force in facilitating the technical iteration of our project.
--input and output
When there are technical gaps in our projects or problems in the experimental validation process, we will take these aspects as the main topic of discussion in our communication with academic experts. Through the feedback from the experts in the relevant fields, we convey the information obtained to the team members of the wet lab or dry lab, helping them to revise and improve the content of the project.
--Clinist
Since our project is planned to be invested in clinical medicine in the future, the medical staff who work in the clinical field are undoubtedly our important stakeholders, and through them we can clearly understand what is needed in the real clinical practice, and help us to modify our project according to the actual needs.
--input and output
As a team with no clinical students, even though we supplemented our knowledge of oncology treatment with self-study during the design phase of the project, the lack of a clinical perspective did pose a number of problems in the beginning of our project. Through in-depth communication with clinists, we were able to supplement this lack of perspective to a large extent, and gain a better understanding of the direction of our future improvements.
--Patient
Due to ethical and psychological considerations, we did not go to the face-to-face level in the actual communication process towards patient group. However, in order to understand the situation and needs of this group who can directly benefit from our CavengerX, we still tried to understand their situation and needs through other stakeholder groups (e.g. clinists).
--input and output
By understanding the patient's needs and situation, UM-Macau further escalated the urgency and necessity of our project and integrated it with information from other stakeholders to provide empowerment and assistance from project iteration, experimental advancement, overall product design, and assisting in digging out the potential of the project's SDGs based on the real needs.
--Society
Cancer, as the common enemy of all human beings all over the world, is undoubtedly a major concern of the whole society in the field of health. In this day, the success of a product depends on its acceptance by the community. Considering this aspect, using the society and the community as a source of feedback will help us to build a more inclusive product based on the society's reaction and expectation.
--input and output
Whether in the form of questionnaires or interviews, obtaining information from the social side of the community allows us to understand the overall perception and attitude of the community towards elements of our project, as well as detecting if there are any obvious misconceptions on certain aspects of the public's perception. By incorporating this dimension into our HP work, it can help us think about how to adjust the perception of using synthetic biology against cancer through education, as well as further iterating our project based on societal expectations and needs.
--Industry
Basic research can help us create an ‘idealised product’ at the lab level, but in order to get our product out of the lab and into practice, using the people from Synbio and Biomedicine industry as our stakeholders can help us polish our CavengerX from a more commercial and industrial perspective, and integrate the information from other stakeholders.
--input and output
Interviews and communications with industrial stakeholders, as well as on-site visit or research in industrial production sites can help us to build our own future project practice scenarios. Moreover, the feedback from our predecessors in the field of biomedical industry-academia-research and translation can help us optimise the design and adjust the shaping of the finished product from a more production-oriented point of view.
--Authority
As a project that is closely related to people's life, property and health, exporting and presenting our project to the government and obtaining their endorsement is a step that cannot be escaped from the landing of our project. Therefore, in our HP work, the authorities are also our important stakeholders, and one of the important tasks of the HP team is to continuously polish our project during the process, and then endeavour to communicate with them in a way that is acceptable and understandable.
--input and output
As the nature of this stakeholder group is very different from the others involved, our work in this session will centre on honing our output and anticipating the information we will receive. For example, using the white paper approach, we aim to profile our project to government authorities and do our best to allay the concerns, remove as many barriers as possible to the progress of our project.
Integrated Human Practice
iHP basis
During the process of putting the scientific theory we learnt into practices in lab and finally in the society, we keep looking for and verifying the valuesor impact of each part of our project from “subjective” to “relatively objective”, “scientific” to “social”, “dependent” to “interdependent”, and “theoretical” to “practical” perspectives, via the process of bidirectional communication with the stakeholders from different sectors at different stages. At the same time, we are acting as a hub to balance the interacting effect and collision of the values from different stakeholders and decide which of these values to be integrated and considered into our project.
Hypothesis, Model, and Methods
Generally speaking, for any activities or tasks we conducted, no matter in wet lab or human practices or dry lab of any subobjectives at any stages, we could apply a universal formula of scientific research which firstly identify their basic Hypotheses, and then we select and establish suitable Model and Methods to prove or dissolve them. For our integrated Human Practice, they were specifically referred to:
1. Hypothesis
which can be equalized as the foundational values or goals that we want to actualize or testified in the end of each task. The main hypotheses of CavengerX are:
- Internally, each part of the mechanisms and theories underlies the novel exosomal tumour therapy using bidirectional calcium overload platform(CavengerX)are able to work technically successfully.
- Externally, the theory, intention, and consideration behind the CavengerX are able to function well into the ethical, political or economical framework of the society.
Figure 2.1.1. The Main Values of our iHP Work Constitution
After the main hypothesizes of our project were identified, we stratify our primary goals into secondary goals from five stages included in the three phases labeled as:
The core of a project is to identify problems and then solve them. Having a clear understanding of the problems we are facing and strengthening the coupling between our projects and the needs are indispensable parts of integrated human practice. Through our two-way communication in this dimension, combined with the information of our target audience and the result-oriented nature of our projects, we are able to use our projects to influence the outside world while also optimizing our projects in terms of our goals.
As the beginning of the engineering cycle, a good project design is the foundation of CavengerX's ability to function and meet its needs. However, the existence of the cycle means that the design of a project cannot be perfect from the beginning, and it is difficult to optimize the iterate on it with only the team's own wisdom. Therefore, it is important to align the work of iHP with the purpose of re-design, and to leverage the interactions with those outside the team to maximize intelligence of our integration with the community.
In our overall project cycle, to validate the specific functions of our modules, it is necessary to design an elaborate experimental process, so that our calcium overload platform we built can tell the outside world with convincing data that our product is useful. In the experimental process, bottlenecks still exist due to the inherent gap and uncertainty between the observation and the micro-mechanism. Therefore, in the course of our iHP work, seeking direction from the outside to improve the experimental methodology also constitutes an important part.
As a sustainable iGEM project, planning for the future of CavengerX must not be neglected. Therefore, in the post-iGEM dimension, we focus on closing the loop of the industry- academia -research cycle, and draw on real-world industry wisdom based on practical application and industrial production to help us further complete the conception, decision and packaging of the project's future form, so that our engineering cycle can go beyond the results of the lab and into the consideration of the actual production.
CavengerX aims to provide humanity with a powerful tool to say ‘goodbye’ to cancer in the future, meanwhile a tool needs to be accepted and monitored by the external society as well as by governmental authorities. Therefore, in this section, we will try to establish an effective two-way communication channel with these more inaccessible dimensions with our currently existing content and concepts on the framework of our work, and give us guidance from a more authoritative point of view.
Figure 2.1.2. The detailed introduction of our phase I to phase III workflow.
2. Model
which is a sort of abstract logical framework or outline that we construct to follow and determine the core reasoning process and derivative correlation of our hypothesis/goals/values; the crude models and principles for our iHP were like:
- Inspiration → Reflection → Actualization
- understand what our values → understand what society desires → distinguish the difference → transmit the compromised value into the project → repeat this cycle
- Which values to be prioritized (achieved) in our project / what compromises to be made
- Reach the goal or not? How and why do we adjust?
- Explore wider and deeper interaction / reflect in a larger scope (with the public):
→ Regulation, policies, and markets
→ Compared with alternative solutions besides synthetic biology
After several loops of discussion and considerations, we concluded and organized this model with more logical correlations and more explicit dimensions of the iterations as below:
Figure 2.1.3. iHP workflow model of CavengerX.
For a certain stage of our iHP or project progress, after targeting the stakeholders and selecting a specific methods (exclaimed in the next part) to establish the communication between us and them, we would express our perception or the recognition of the specific problems that we encountered at the current stage to the relevant stakeholders, while grasping and interpreting the social perception or desires from their perspectives of profession. Firstly, we would validate the exact values that we should focus on or prioritized, and throughout the progress of communication and discussion, we would try to uniform or perfect our norms and pursue the improvement of the hierarchized strategies. After obtaining potential plans for these values, we would identify the limitations of these values and how they may clash or interact with the values from other stakeholders of different stages and sections, throughout the loop of conducting and practicing them no matter in wet lab, dry lab or HP, as well as reflecting the feedback to the stakeholders we found and validating the actual effect. Finally, we would see whether this process could provide some inspiration for the next stage values chosen.
3. Methods
which can be recognized as the objects/stages-oriented form of the specific end-to-end activities that engage those stakeholders into our interaction and promote the communication under the framework of our modeling. For us they are referred to:
- Questionnaires/surveys
- Interviews
- Industry field trip
In addition, all these three parts also align with the essential HP principles, which means we ensured our work to be acted: Respectfully, responsibly, inclusively, sustainably, creatively, and specifically.
Phase1
Cancer Treatment Public Research Report
Since CavengerX is essentially a project to provide health benefits to the general public, in our Phase I pre-project research phase, based on our methodology around iHP, we conducted a social survey from the perspective of the general public, using questionnaires and oriented towards the ultimate goal of the project, on the general public's perceptions of cancer treatments and expectations of new anti-cancer therapies in the future. We carried out a social survey covering as much as possible all age groups and education-level backgrounds.
The survey results show that the public generally recognizes the need for innovative anti-cancer therapies, especially from the perspective of the advantages of targeted therapies. In the face of the perception of traditional anti-cancer therapies, 82.8% of respondents are aware of the common side effects of chemotherapy, such as nausea and vomiting, and 64.5% understand that it may lead to bone marrow suppression, indicating that the public understands through the various channels of information exchange in today's society just how much fear traditional therapies have brought severe side effects to the public.
Figure 2.2.1. Respondents' knowledge and cognition of side effects of various cancer therapies.
At the same time, 75.3% of the interviewees we surveyed believe that precision targeted therapy is highly selective and can specifically act on cancer cells, and 73.1% believe that it has relatively few side effects, which shows that the public has expectations for the development of new oncology therapies, which can satisfy them to overcome their fear of cancer and the consequences of its traditional therapies.
Figure 2.2.2. Public perceptions and expectations of the benefits of targeted cancer therapies.
However, the public believes that the high cost of treatment remains a major burden amongst the many therapies available for cancer today, with 64% of respondents believing that it is too much of a financial strain on the individual patient, and 80% believing that the cost poses a huge burden on the family, further supporting this view against financial pressures.
Figure 2.2.3. Public perceptions and considerations of the major burden of cancer for patients.
There is no doubt that the concerns about treatment efficacy, side effects, and cost of treatment expressed during the pre-project research phase of our CavengerX project have truly revealed the need for an innovative cancer therapy development programme, and the feedback we have received from the public has provided us with a pathway for future project development and possible needs-based iterations.
The general assessment of our project
Evaluating the effectiveness, safety and affordability of treatments
"We need to evaluate whether our method can kill cancer cells more efficiently or with fewer side effects compared to existing treatments. In addition, the clearly confirmation of both the effectiveness and safety of our project are also important."——Dr. Jingjing Liu
"There are two aspects that most patients are concerned about, one is death and the other is the pain of the disease. Therefore, we should focus more on prolonging survival and improving quality of life."——Prof. Kai Miao
Expectations for the treatment modalities and outcomes of our project
Dr. Jingjing Liuprovided valuable suggestions for the future development of our project. He proposed that we should explore whether this treatment method demonstrates outstanding effectiveness against specific types of cancer or particular cancer cells. He also raised the question of whether the density of clustered cancer cells affects the efficacy of ultrasound treatment and what the critical threshold for this effect might be. Lastly, he inquired whether our treatment could be used independently or in combination with other therapies to enhance its effectiveness in clinical applications.
Prof. Qiang Chen believes that immunotherapy is the most popular treatment today. But it may also cause cancer cells to evolve and become drug-resistant, which is the biggest drawback of tumour treatment. The best way is to detect the tumour at an early stage and intervene through surgery. However, for the middle and late stage cancers, it is more important to regulate the autoimmune system to attack the tumour. The main research direction is how to inhibit the immune escape of the tumour. However, currently, the beneficiary population of the immunotherapy vary in different cancer and considerable amount of patients are not responsive . For example, the treatment efficiency of melanin and lung cancer can reach 40%-50%, but liver cancer can only reach about 10%, and there is a big gap between solid tumours and non-solid tumours. He therefore hopes that our approach will solve part of the above problems.
Prof. Kai Miao suggested that individualized differences of tumours need our attention, and we should think about how to solve the problem of individualized differences of patients caused by tumour heterogeneity in the drug research process. He believes that we can research on patients' conditions to develop different treatment plans.
Chao Pan believes that iGEM's previous cancer-related projects have focused on the modification of engineered bacteria, such as allowing engineered bacteria to act as delivery carriers for common cancer drugs. Last year, the iGEM team in BNUZH carried out iron death, which is a relatively unique approach, while the cell death of Huazhong University of Science and Technology is also looking for newer therapeutic modalities outside of the conventional approach. He believes that these new ways of dying may become a path of innovation.
Prof. Jian Renbelieves that despite the fact that we have chosen to use the currently popular strategy of ion regulation to manipulate the death of cancer cells, our project requires a clearer target cancer or solid tumour, because there is a very wide variability between different cancers and their subtypes. Our project is therefore considered as a 'broad-spectrum' method.
Expectations regarding research modalities
Prof. Jian Renresearch focus is on bioinformatics analysis, he believes that the development of future cancer therapies must be supported by big data and the use of bioinformatics tools. Since our project could involve the use of small molecules for exosome modification, Prof. Ren emphasized the importance of high-throughput technology in screening small molecules for anticancer targeting, and suggested that we should try to use high-throughput methods to screen small molecules that are suitable for exosomes and capable of targeting markers specific to different cancer cells in the next iteration of the project, from small to large scale, to solve the problem that the specificity of our project is still insufficient.
Phase 2
1.Is there a plateau period for the effects of calcium ion concentration? If so, how can the plateau period be addressed?
"The calcium ions may develop tolerance, and the tumour cancer cells may also release some corresponding channels, as in the case of antibiotic resistance, which creates a drug resistance mechanism. "——Prof. Qiang Chen
"There might be a rate-limiting step in the chemical reaction by overloading calcium ions, so that the calcium ions reach a plateau at a certain amount and cannot act further." ——Chao Pan
Improvement: Whether the plateau period exists or not still needs to be verified during our clinical trials. Also our therapy can be used as a kind of adjuvant therapy to conventional therapy, for example, if the cancer cells may not be able to completely killed using chemotherapy methods, we can use our method to continue to kill them, and even though there may be a plateau in the concentration of calcium ions, while some of the antigens can still be released to cause a wider range of immune responses.
2.How to measure and control calcium ion concentration?
"You need to consider the time of induced death to avoid the effect of too long induction time on the human body. Because the cells themselves have some ways to balance the ion overload, it takes some time to induce cell death. If the time is too long, the body's own immunity will also be affected."——Chao Pan
"In terms of detecting intracellular calcium ions, I suggest that you can use specific calcium probes. For example, there is a specific calcium sensor (such as Fluo-4) that can bind calcium and emit fluorescence, allowing us to determine the intracellular calcium concentration. Also, the issue of intracellular and extracellular calcium concentration and its effects need to be point out, you need to understand how to maintain calcium gradients and perform apoptosis experiments to determine cell death."——Prof. Assaraf
Improvement: We controlled the influx and concentration of calcium ions by the presence or absence of ultrasonic stimulation. We chose a fluorescent calcium indicator to indicate changes in the concentration of calcium ions through changing fluorescent signals, and an ion-selective electrode to directly measure the concentration of calcium ions in solution.A fluorescent calcium indicator is a molecule that reflects changes in calcium ion concentration through a fluorescent signal. When a fluorescent calcium indicator binds to calcium ions, its fluorescent properties change, such as fluorescence intensity, wavelength, or lifetime. By monitoring changes in these fluorescent signals, the concentration of calcium ions can be measured indirectly. This method is highly sensitive and real-time and is suitable for the study of intracellular calcium signalling dynamics. In contrast, an ion-selective electrode is a sensor that can directly measure the concentration of specific ions in solution. For calcium ions, calcium selective electrodes can be used to measure their concentration. Ion-selective electrodes detect the ion concentration by reacting specifically with the target ion in solution, producing a change in potential. This method is highly selective and accurate and is suitable for making precise measurements of ion concentrations.
3.How our project targets solid tumours
"The main reason why leukaemia can be cured is because it has a very good target that can be identified. However, your project aims to have better application on the solid tumour, which requires different targeting methods for various kinds of cancer cells. There may be only 10% of solid tumour cancer cells that have fixed targets. Currently, your project still faces the problems for the insufficient specificity in targeting cancer cells. Maybe you could try using iRGD to help you targeting tumours."——Prof. Haiyan Zhang
"The most important factor is the specific targeting, for example, whether your drug can reach the organ where the tumourtumour is located without affecting other organs. And it is relatively easy to target the lungs and liver, while the bone and brain are more difficult."——Prof. Kai Miao
"You should consult more literature, narrow your focus to proteins, identify their binding targets with cancer cells, and ensure that relevant structures have accessible data in the public domain. Your project has significant potential, but several key issues must be addressed to ensure its smooth progress and effectiveness."——Prof. Henry
"The regulation of ion-related channels are also one of the hot spots of research, and theoretically speaking, your ideas are relatively realistic. In terms of tumor cacncer treatment, the major challenge is how to control the specific targeting, so that it can really target tumor cells and can reduce the potential side effects. Actually, the most important consideration in clinical practice is how to find suitable patients for individual treatment for each patient. Only precision therapy can control the tumor in different patients, and then reduce controllability and the related toxicity and side effects in clinical practice. "——Dr. Hao Yan
Improvement：We achieve targeting through the use of iRGD, a tumor cell specific membrane-penetrating peptide. Integrating the iRGD sequence onto the surface of the exosome enables the exosome to be specific for tumor cells. iRGD achieves precise recognition and targeted delivery of the exosome to tumor cells by binding to specific receptors on the surface of tumor cells.
4.How do exosomes get into cancer cells? Endocytosis or otherwise? Is it possible to use one's own exosomes to increase efficiency?
"The exosomes you used are weakly phagocytosed by the cancer cells, but the self-cells phagocytose their own exosomes more efficiently, so perhaps this is a way to improve the therapeutic efficacy. Secondly, the way in which the exosomes are directedtargeted to the tissue is also important."——Prof. Qiang Chen
"It should be sufficient by the carrier to combine proteins with exosomes, these exosomes can penetrate cancer cells and deliver the target proteins. Your team need to realize the importance of determining whether exosomes enter cancer cells through endocytosis or other pathways. "——Prof. Henry
"You need to know the molecular weight and other properties of proteins, such as the properties and characteristics of transmembrane domains, for proteins to enter the membrane smoothly. And you need to understand the process of exosome formation and its role in biological processes. For example, in wound healing, lysosomes play a role in the delivery ofexosomes to wounds, while proteases help tissue regeneration."——Prof. Assaraf
Improvement: Exosomes bind to receptors on the surface of cancer cells and enter the interior of the cell via a receptor-mediated endocytosis pathway. This process involves specific recognition and binding of the exosome to the receptor, which facilitates the uptake of the exosome by cytosis. In addition, we found that the exosomes can enter cancer cells by other mechanisms, such as fusion with the cell membrane to release their loaded material, or by direct cell-to-cell delivery.
Regarding the use of self exosomes for efficiency, engineering the patient's own exosomes to make them more targeted and therapeutically effective could be explored. By integrating specific targeting molecules or drugs onto the surface of the patient's own exosome, the specific binding of the exosome to cancer cells can be improved, thereby enhancing therapeutic efficacy. In addition, the risk of immune rejection and other adverse reactions can be reduced by utilising the patient's own exosomes, which are more compatible with the patient's tissues. Thus, treatment with autologous exosomes can increase therapeutic efficiency and reduce potential adverse effects. But we were unable to genetically modify auto-exosomes to carry MscS and hTRPC1 calcium channel proteins in the human body; therefore, we do not consider the use of auto-exosomes in our project.
5.How can we verify that exosomes actually carry ion channels?
"You should conduct staining experiments and employ various methods to confirm that exosomes can indeed enter cancer cells and to identify their targets within these cells. Additionally, You need clarify the specific procedures and detection methods for each step of the experiment, such as using Western blotting and transmission electron microscopy (TEM) for detection."——Prof. Henry
"Whether these ion channels can actually be carried by the exosomes, and whether they are imported efficiently enough, are all things that you need to continue to test."——Prof. Qiang Chen
Improvement：In the Western Blot assay, we determine whether the exosome is produced by detecting the exosome marker proteins CD63 and CD81, and whether the exosome carries our target proteins MscS and hTRPC1 by detecting the HA markers linked to the MscS and hTRPC1 proteins.
6.What is the specific mechanism of action of ultrasound, whether whole body ultrasound or localised is used? How is the intensity controlled?
"The use of the ultrasound stimulation, such as the choice of location and energy level of the ultrasound needs to be redefined."——Prof. Haiyan Zhang
"You need to further clarify its specific mechanism, particularly how ultrasound influences calcium ion channels and why calcium channels are preferred over sodium channels. "——Prof. Henry
Interview with Prof. Haiyan Zhang
Ultrasound acts on cells or tissues through mechanical vibration and can trigger changes in the cell membrane, such as opening of channels or alteration of intracellular structures.
Controlling the intensity of ultrasound is essential to ensure the effectiveness and safety of the treatment. The intensity can be controlled in the following ways:
①Output power control: Adjust the output power of the ultrasound device to control the intensity.
②Treatment time control: control of ultrasound effect time, can indirectly control its intensity.
③Distance control: The intensity of the ultrasound decreases as the distance increases, ensuring that the distance between the source of the ultrasound and the treatment area is appropriate.
Phase 3
For the selection of exosomes and mesenchymal stem cells (MSCs)
For those who support MSCs
"MSCs will be more compatible with the immunosuppressive environment in which cancer cells live, allowing our treatments to have a better outcome"——Prof. Renhe Xu
"The T-MSC cells we have developed are more active, age slower, and do not express inflammatory factors such as IL-6 compared to MSCs , are less immunogenic and safer to be used in this project."——Dr. He from Imstem
For those in support exosomes
"MSCs may not be able to enter solid tumors and have major safety concerns."——Prof. Haiyan Zhang
" Exosomes as drugs are a much cheaper method and supported by many papers in the scientific literature, they are also membrane permeable and may be able to reach the site of action better."— —Prof. Haiyan Zhang
"The exosomes we used are weakly phagocytosed by the cancer cells, but the self-cells phagocytose their own exosomes more efficiently and safer. "——Prof. Qiang Chen
"Exosomes can achieve specific targeting by wrapping a layer of protein around the periphery, while stem cells will be relatively less specific." ——Prof.Kai Miao
"Exosomal approach may be more mature, while stem cell technology itself may have many risks of drug resistance." ——Chao Pan
"The adult stem cells are more dangerous because they are not the patient's own cells. If ‘off-the-rack stem cells are used, the way the stem cells are modified and the in vivo experiments need to be examined and evaluated." ——Chao Pan
For the suggestions
Prof. Haiyan Zhangbelieves that we can use surgery or other surgical means to complement the treatment and help our exosomes to better enter the solid tumor.
Chao Pan believes that there are two essential considerations when pondering this question; one
is effectiveness, and the other is safety. Efficacy is about which treatment is more efficient,
which means that we need to compare the amount of calcium ion channels that are induced. In terms of safety, Pan Chao suggested that we should look for reviews on the safety of exosomes to assess this.
Professor Chen Qiang believes that the exosomes we used are weakly phagocytosed by the cancer cells, but the self-cells phagocytose their own exosomes more efficiently, so perhaps this is a way to improve the therapeutic efficacy. Second, the way exosomes are directed to tissue is also important. Furthermore, whether these ion channels can actually be carried by the exosomes and whether they are imported efficiently enough are all things that we need to continue to test.
For the clinical treatment
The interview with Dr. Dixiao Zhang focused more on the common problems in the clinical treatment of cancer. First, about the major factors for choosing a patient's treatment, Dr. Zhang said that she will identify the cancer stage according to the imaging examination and the progression of the disease to determine the treatment strategy. In addition, the availability of drugs, affordability of the cost, medical insurance policy, patient acceptance, treatment convenience will also be considered. Regarding the issue of communicating with patients and their families, Dr. Zhang said that she will first inform them whether they are targeted drugs, chemotherapy drugs, or immune drugs. Also, she will explain the side effects of the drug to increase the family and the patient's acceptance. More importantly, it is necessary to pay attention to the psychological problems of the patients themselves and their families.
Dr. Zhang also said that he believes that exosome therapy is relatively new and theoretically feasible. At the same time, it is recommended that we expand the experiment of this therapy to different types of tumor, in hopes that this therapy can achieve better results in solid tumors.
The interview with Dr. Liu Dongbo provided a comprehensive overview of cutting-edge cancer treatments and their effectiveness. Dr. Liu emphasized that cure rates for cancer have significantly improved over the past few decades, with some types of cancer now having cure rates as high as 90%. They highlighted that the choice of treatment depends on various factors, including the type and stage of cancer, as well as the patient's overall health and personal preferences.
Dr. Dongbo Liudiscussed several innovative treatment approaches, including immunotherapy, targeted therapies, and precision medicine. Immunotherapy, which harnesses the body's immune system to fight cancer, has shown remarkable results in certain types of cancer, particularly melanoma and lung cancer. However, it can develop drug resistance over time. Targeted therapies, designed to attack specific molecular targets in cancer cells, have also proven effective in many cases, with new drugs constantly being developed. Dr. Liu noted that precision medicine, which tailors treatment to an individual's genetic profile, is becoming increasingly important in cancer care.
He also highlighted oncolytic viruses as a promising area of research. These viruses selectively infect and destroy cancer cells and can be combined with immunotherapy for potentially enhanced effects. In radiotherapy, proton therapy offers more precise treatment compared to traditional radiotherapy, minimizing damage to surrounding tissues. However, it's expensive and primarily suitable for tumors near sensitive organs. Traditional radiotherapy affects surrounding tissues more but is simpler to administer and suitable for less precisely targeted areas.
Chemotherapy remains a cornerstone of cancer treatment, often used in combination with other therapies. It can be administered intravenously or orally, though intravenous administration is often preferred due to better bioavailability. Drug resistance is a significant challenge, with an average resistance time of 19 months for third-generation EGFR tyrosine kinase inhibitors in lung cancer.
Combination therapies, such as chemotherapy with immunotherapy, show promise in treating advanced cancers but present challenges in determining the individual contribution of each therapy. Novel drug delivery mechanisms, like antibody-drug conjugates (ADCs), involve a drug payload, a linker, and an antibody targeting tumor cells, allowing for more precise drug delivery.
When it comes to communicating with patients about their treatment options, Dr. Liu emphasized the importance of clear, honest, and compassionate communication. They stressed the need to provide patients with accurate information about their prognosis and treatment options, while also offering hope and support. Dr. Liu mentioned that they often use visual aids and analogies to help patients understand complex medical information.
Regarding factors that influence treatment choices, Dr. Liu highlighted the importance of considering the patient's overall health, age, and personal preferences. They noted that some treatments may be too aggressive for older or frail patients, while younger patients might be candidates for more intensive therapies. Dr. Liu also mentioned that financial considerations and access to specialized treatments can play a role in treatment decisions.
Dr. Liu elaborated on treatment selection factors, which include efficacy, safety, cost, patient health, age, preferences, insurance coverage, treatment goals (curative vs. palliative), and cancer type and stage. Early-stage cancers often prioritize surgery, while intermediate stages may use treatments to shrink tumors before surgery. Late-stage cancers typically focus on palliative care, chemotherapy, immunotherapy, and localized radiation.
The interview touched on the challenges of treating advanced or metastatic cancers. While cure rates for these cancers are generally lower, Dr. Liu emphasized that there have been significant advancements in prolonging life and improving quality of life for patients with advanced disease. They mentioned that combination therapies, which use multiple treatment modalities, have shown promise in treating some advanced cancers.
Dr. Liu emphasized that treatment approaches vary significantly based on cancer stage and type. For instance, lung cancer five-year survival rates range from about 80% for early-stage to 18% for late-stage disease, despite advances in treatment modalities. He also mentioned the importance of following established guidelines like CSCO (Chinese Society of Clinical Oncology) and NCCN (National Comprehensive Cancer Network) for treatment recommendations at different stages.
Cancer Network> for treatment recommendations at different stages.
Dr. Liu also discussed the importance of supportive care and palliative treatments in cancer management. They emphasized that managing symptoms and side effects is crucial for maintaining patients' quality of life throughout their cancer journey. Dr. Liu mentioned various supportive care options, including pain management, nutritional support, and psychological counseling.
When asked about a novel calcium overload cancer therapy, Dr. Liu expressed cautious optimism. They explained that while the therapy shows promise in laboratory studies, more research is needed
to determine its effectiveness and safety in humans. Dr. Liu emphasized the importance of rigorous clinical trials in evaluating new cancer treatments and cautioned against relying on unproven therapies.
The interview concluded with Dr. Liu's thoughts on the future of cancer treatment. He expressed optimism about ongoing research in areas such as gene therapy, nanotechnology, and artificial intelligence in cancer diagnosis and treatment. Dr. Liu predicted that cancer care will become increasingly personalized in the coming years, with treatments tailored to each patient's unique genetic and molecular profile.
Throughout the interview, Dr. Liu emphasized the importance of a multidisciplinary approach to cancer care, involving collaboration between oncologists, surgeons, radiologists, and other healthcare professionals. They also stressed the significance of ongoing research and clinical trials in advancing cancer treatment and improving patient outcomes.
Collaboration and raise to a higher level
Introduction
After the 2024 iGEM Greater Bay Area Synthetic Biology Industry-Academia-Research (iGBA) Forum in this summer(more details see in SDG page), JLU-NBBMS team launched an initiative for an Biosafety & Bioethics white book writing planning, calling of several Chinese iGEM teams included UM-Macau iGEM to participate and brainstorm together. We settled up the main objectives and main focus of this white paper, which is about an overall evaluation of the feasibility of our project in the context of the bioethics and biosafety, according to the investigation of the national or international frameworks that are applicable to our CavengerX projects, in addition to the novelty and new inspiration generated from our CavengerX and the oncology villages to which our project belongs. We actively participated in the following editing, revising, and auditing process as we thought this module perfectly complemented the final stage and the stage before the final of our iHP cycle. We could examine the problems and risks that would potentially occur in the process of execution of our project eventually in the society and community regarding the current healthcare environment, clinical biosafety standards or the degree of social ethical acceptability.
This UM-Macau white paper presents a comprehensive analysis of the issues surrounding CavengerX using engineered exosomes and synthetic biology to induce calcium overload in cancer cells. As cancer remains a leading cause of death worldwide, with many current treatments facing limitations such as drug resistance and severe side effects, there is an urgent need for innovative therapies. Our proposed calcium overloading project represents a cutting-edge approach that combines precision oncology with synthetic biology techniques. However, the novelty and complexity of this approach necessitate a thorough examination of its various implications, from regulatory and ethical considerations to technical challenges and potential societal impacts.
Purpose and Function
Based on the method at the beginning of the HP part, the dimension of authority is also our targeted element, thus the purposes of our white paper book is used as a tool from this dimension’s consideration:
- To provide a comprehensive overview of the calcium overloading project and its potential implications.
- To identify and discuss the various challenges and considerations associated with developing and implementing such an innovative therapy.
- To explore the existing regulatory frameworks from the government level, as well as to highlight areas where new regulations may be needed.
- To stimulate discussion and collaboration in addressing the complex issues surrounding this project with authority,make our attempt to use it as a tool between us and the government.
- To serve as a roadmap for researchers, policymakers, and other stakeholders involved in similar innovative cancer treatment approaches.
1. Village Introduction:
This section outlines the current challenges in cancer treatment and introduces the concept of precision oncology. It highlights the unsolved problems in cancer therapy and presents new ideas in oncology and precision oncology. The advantages of integrating precision oncology with traditional approaches are discussed, emphasizing improved targeting, personalized treatment, and enhanced safety.
2. Project Introduction:
This part provides an overview of the calcium overloading project using engineered exosomes and synthetic biology. It covers:
· Target Population & Key Stakeholders
· Highlights of the Project, including its innovativeness and strategies for improving cancer specificity
· Social Impact from different perspectives (public health, economic, individual/caregiver)
· Risk Mitigation Strategies
· Biosafety Measures
3. National/International regulations for Bioethics & Biosafety:
This section addresses the regulatory landscape relevant to the project:
· Regulations on Exosomes and Extracellular Vesicles
· Genetic Engineering and Synthetic Biology Oversight
· Clinical Trials and Ethical Oversight
· Other Relevant Frameworks (e.g., data privacy laws, biomarker validation)
· Future Considerations for regulations in areas like manufacturing, containment, environmental impact, and patient access
Our white paper book has explored the myriad issues surrounding our calcium overloading project for cancer treatment. By examining the project from various angles - scientific, regulatory, ethical, and societal - we have highlighted both the immense potential and the significant challenges associated with this innovative approach.
The integration of precision oncology with synthetic biology techniques offers exciting possibilities for more effective and personalized cancer treatments. However, it also raises important questions about biosafety, ethical considerations, and regulatory oversight. Our analysis reveals that while existing regulatory frameworks provide a foundation, there are still significant gaps that need to be addressed, particularly in areas such as exosome manufacturing, environmental impact assessment, and long-term safety monitoring.
This paper also serves as an inspiration for future research and policy development. By identifying key areas of concern and potential solutions, we hope to stimulate further investigation and collaborative efforts to address these challenges especially between us and government.The interdisciplinary nature of this project highlights the importance of breaking down barriers between different fields of study and fostering cooperation between diverse stakeholders.
In conclusion, while our calcium overloading project faces significant challenges, it also represents an exciting frontier in cancer treatment. By proactively addressing the various issues outlined in this white paper, we can work towards developing safer, more effective, and ethically sound innovative therapies. This paper serves as a call to action for researchers, policymakers, and other stakeholders to engage in thoughtful and comprehensive consideration of the implications of such groundbreaking approaches to cancer treatment.
