Team:SYSU-Medicine/Integrated Practices
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INTEGRATED HUMAN PRACTICE
1. Conduct a survey
All the surveys followed randomized design.
For our first questionnaire, more than 500 people took part. Among them, 313 with medical background while 223 without medical background. We asked that if they were given a fund to put into therapeutic research, how they would distribute it. The majority of survey participants picked malignant tumor as an area of priority whether they had a medical background or not. This made us more determined to research in malignant tumors.
Question: If you were given a fund to put into therapeutic research, how would you distribute it?
People without medical background
People with medical background
After reviewing projects completed by other iGEM teams in the past few years, searching for papers in many areas and discussing between team members, we finally determined to focus on the ‘silver bullet’ to malignant tumors——Oncolytic virus.
Based on the direction of our project, we conducted our next survey. We invited 500 people to participate in it. These are two main questions from the questionnaire.
Question: Have you ever heard of Oncolytic Virus?
People without medical background
People with medical background
According to the result, only 11.8% of people without medical background had heard of oncolytic virus before. Even for the people with medical background, only half of them knew about oncolytic virus. This suggested that we should make an effort in the propaganda of our product.
Question: Are you worried about safety problems of Oncolytic Virus?
People without medical background
People with medical background
Regardless of people’s medical background, only approximately 3% of them chose “no concern at all”, which means, the overwhelming majority of survey participants concerned about the safety of oncolytic virus. Therefore, one of our goal was to improve its safety and eliminate public concern for oncolytic virus.
2. Interview with Professor Penghui Zhou
Once the research direction was put forward, we made our first interview. We interviewed professor Zhou who engaged in tumor immunology research. After consulting with Professor Zhou about the prospects of tumor immunology and oncolytic virus therapy, we determined the aim of our research.
Zhou penghui
professor and doctoral supervisor of SYSU Cancer Centre. He has a long research history in tumor immunology and tumor immunotherapy and his works are published on Nature，Proceedings of the National Academy of Sciences，Clinical Cancer Research and other famous magazines.
Q1: professor Zhou, you are an expert in the field of immunotherapy. We would like to know the advantages of immunotherapy over other classical tumor treatments.
Professor Zhou: As a kind of developed tumor therapy, tumor immunotherapy has the potential to completely cure malignant tumors, especially some patients with advanced malignant tumors. The side effects of immunotherapy are also much smaller and more manageable than conventional cancer treatments such as chemotherapy and radiotherapy.
Q2：At present, we are also committed to publicizing oncolytic virus to the public by spreading scientific knowledge and eliminating people’s confusion, so that the public will not be afraid of the word "virus". What’s your view and Suggestions?
Professor Zhou：The key to making the public not afraid of virus is the curative effect. If the modified oncolytic virus can obtain a good therapeutic effect or adjuvant therapeutic effect, the public's "fear" will disappear naturally.
Q3: We know that one of the mechanisms of oncolytic virus is the activation of the immune system. What do you think are the main differences between oncolytic virus and other popular immunotherapy?
Professor Zhou: Presently, oncolytic virus is more of an auxiliary means and plays a role of a "trigger". The effect of oncolytic virus alone is relatively low. More often than not, the role of the oncolytic virus is to initiate the body's initial immune response to maximize the effectiveness of subsequent immunotherapy.
Q4: It has been decades since the development of oncolytic virus, but it has still not become the main force of tumor therapy. What do you think of it?
Professor Zhou: The current oncolytic virus cannot stimulate a strong enough tumor immune response from the perspective of tumor immune activation. From the point of direct oncolytic effect, the unmodified oncolytic virus cannot kill 100% of the tumor inside human body. Oncolytic virus can carry tumor antigens to enhance the killing effect and anti-tumor immunity of the body, but its main functional part is the virus, so the immune response of the body cannot be too strong, otherwise the virus would be killed by the immune system of the body before it reaches the tumor site. At the same time, it can’t be too weak for it couldn’t play a very good role in tumor killing. Perhaps we could consider inducing the expression of tumor antigens carried by oncolytic viruses to be highly expressed in the right place to enhance the tumor killing effect.
Q5: Could you comment on the current safety of immunotherapy or the potential risk of oncolytic virus?
Professor Zhou: The safety of an immunotherapy needs to be tested clinically. The main purpose of existing immunotherapy and oncolytic virus is to activate the tumor immune system to kill tumor tissues. Therefore, the most likely potential risk is that the overresponse of the immune system will lead to an overreaction which may cause damage to the patient's body. But now, there is a complete set of guidelines and methods, both at home and abroad, to deal with the body damage caused by the possible immune overreaction.
3. interview with Professor Guangmei Yan
After choosing oncolytic virus for our research direction, our second question came, ‘What kind of virus should we choose? How can we engineer this kind of virus?’ Our public survey reflected that most survey participants hoped OVs can kill tumor cells thoroughly without any tumor cell left, or simply, can kill many types of tumor cells. So, we wanted to start from its lethality and spectrum of antitumor property. We then consulted with Professor Yan who works on oncolytic virus about the questions above. After the conversation, we decided to pick M1 virus and directed evolution for the direction of our research to study its spectrum of antitumor property.
Guangmei Yan
former vice President of Sun Yat-Sen University, professor of pharmacology of Sun Yat-Sen University, doctoral supervisor. His main research interests are "oncolytic virus therapy and induction differentiation therapy for malignant tumor therapy" and "molecular genetic mechanism of ischemic hypoxic brain injury".
Q1. In your opinion, what are the characteristics of oncolytic virus?
Professor Yan: Oncolytic virus therapy is a combination of immune therapy, gene therapy and targeted therapy, which can target to malignant tumor cells and infect them by selective replication and thus increase the local drug dosage. By directly dissolving tumor, activating the antitumor immune response, destructing therapeutic genes expressed in tumor blood vessels and a variety of mechanisms, oncolytic virus finally kill the tumor.
Q2. What is the current situation of oncolytic virus?
Professor Yan: Dozens of oncolytic viruses have made varying degrees of progress in phase i-iii clinical trials. Among them, Amgen's oncolytic virus drug T-VEC was first approved in the United States and Europe in 2015.
Q3. Is there anything that oncolytic virus should be improved at this stage?
Professor Yan: The problem of poor efficacy in clinical trials still haunts its development and application. This may be because most oncolytic viruses are pathogenic viruses (herpes simplex virus, poxvirus, poliovirus, etc.) that have been genetically engineered to remove virulent genes and become attenuated. Few wild viruses (reovirus, Malabar virus, Newcastle disease virus, etc.) have not been reported to cause human disease, indicating that their virulence is relatively weak. In addition, the rapid neutralization and elimination of the virus in the human body, the inability of the virus to penetrate deep tumor tissues and effectively spread in tumor patients also limit the efficacy of oncolytic virus in tumor patients
Q4. We are hesitating to pick a virus to study, do you have any recommendation?
Professor Yan: After more than 10 years of research in our laboratory, we have identified a natural oncolytic virus M1 and elucidated its molecular mechanism of selectively killing tumors and not affecting normal cells.The virus is about to start phase I clinical trials and has good research prospects.
4. collaboration with other igem teams
We attended the after-iGEM conference in Shenzhen to listen to the voice 2018 iGEMers had about their iGEM journey. We realized that this wasn’t just a contest, but a place where we share exciting thoughts and do amazing things. Later, attending Southern China’s biggest iGEMers get-together was our first thought of collaboration. During the summer, we attended CCIC, China’s largest iGEM conference, looking for help improving our project. What’s more, we also had collaborations with other iGEM teams and helped each other when we had troubles in the experiments.
Written by team members: “IGEM is a community”, our instructor, second-time iGEMer often tells us. The first time I had a feeling of a community was around the beginning of November 2018. When the 2018 iGEMers finished their run and came home. Four teams, including the best in high school group and the second runner-up in undergraduates group, held an after-iGEM conference in Shenzhen to share their experience and. Three of us attended the conference and had our first actual impression about iGEM. We realized that this wasn’t just a contest, but a place where we share exciting thoughts and do amazing things. And we realized that being a part of iGEM, we need to stretch out to other iGEMers as well. Attending Southern China’s biggest iGEMers get-together was our first thought of collaboration. We shared our project and gave some suggestions to other projects as well. “
“Summer vocation in 2019 for us was quite frustrating. We had to move to plan B when plan A was out of option. Plan B required the choosing of drug we wanted to use on the system. At first, we wanted to create a pro-drug on our own based on other pro-drug creating methods. But when we attended CCIC, China’s largest iGEM conference, looking for help making the pro-drug, we found that creating a pro-drug on our own was impossible. So we quickly turned to a drug with an existing pro-drug. The one who gave us the advice was the adviser from CPU. Later, in gratitude of their help, we send them TLR4 plasmids to help them progress in their experiments.”
“The national holiday wasn’t a holiday for our members but was for the companies. That left us in an awkward situation where we used up all our primer but had no where to get more. Luckily, SCUT, also a member of iGEM society, lent us the primer we needed.”
“Our collaboration with other iGEMers not only promoted our decision-making at a turning point, but also drove our experiment schedules on. We all agree that we couldn’t make it without the help of the community. “
team leader sharig our project in the iGEM Southern China regional meeting
team members attending the Conference of China iGEMer Community
team members attending the Conference of China iGEMer Community
5. GCP Office (Good Clinical Practice)
All scientific research is ultimately for the benefit of human society. Before that, we had surveyed the general public and consulted some experts. However, there is a very important link in the pharmaceutical industry chain, which is the department that manages clinical trials of drugs. In order to know the status quo of clinical drug trials and their evaluation and recommendations on our products, we visited to the GCP office of the Cancer Prevention and Treatment Center of Sun Yat-Sen University and consulted the office administrator.
After the conversation, we learnt that previous application of oncolytic virus had a common shortcoming that this kind of therapy could only work locally, lack of the ability to eliminate metastatic cancer. We also knew that the current trend in the clinical treatment of cancer is non-invasive treatment such as oral administration. What made us relieved was that she recognized our safety system as a perfect way to ensure the safety of M1 and made M1 more stable for clinical use. Also, they encouraged us for further study, so we perfected M1 for animal study and other chemotherapy drugs.
Q1: Article 5 “Before conducting a human trial, the expected benefits and risks to subjects and public health should be weighed, and the expected benefits should outweigh the possible damages.”How should the expected benefit outweigh the possible harm be assessed in actual clinical trials?
Professor Cao : This is a matter of principle. The treatment program provided by the doctor must be for the relief or cure of the disease. The clinical trial of the drug can be regarded as a special clinical treatment. At this time, the efficacy and safety of the drug have not been fully verified and it is expected to be effective against the tumor. But whether it will work in humans and its possible side effects are unknown. This is actually a clinical practice with a scientific research and high risk, and any clinical study is designed on the basis that we predict that the effect of treating the tumor outweighs the side effects and damage.
Q2: How important is the role of ethics committees?
Professor Cao: it is very important. The primary responsibility of ethics committees is to review whether the scheme will cause excessive risks to patients, weigh the proportion of risks and benefits, and check the readability of informed consent.
Q3: Do you know about oncolytic virus? have there been any application related to Oncolytic virus recently?
Professor Cao: Our hospital has done a research on oncolytic virus before, but the road was bumpy. Finally, the drug could not be made and marketed. There has also been a recent application of oncolytic virus in the field, but the concept of the treatment cannot really solve the problem of the disease. At present, oncolytic virus is mainly through local injection, so the scope of elimination of the virus is limited. It did not take into account the majority, resulting in metastatic cancer is difficult to eliminate.
Q4: The oncolytic virus we are currently studying is actually selectively recruited locally in the tumor through intravenous injection, which eliminates the previous limitations of oncolytic virus in local injection. Also, we combine with prodrug so that it can kill more cancer cells locally to achieve the elimination of cancer. What do you think of its prospect?
Professor Cao: It’s a fantastic idea. It would be safe for patients if your drug can target on tumor cells specifically as well as only kill the tumor cells without damaging normal tissues. Although it would be little difficult to achieve all the goals at the same time, it's worth trying. I encourage you to keep this study and test it on animals when your virus product is ready.
Q5: What is the current trend in the clinical treatment of cancer?
Professor Cao: Currently, non-invasive treatment is preferred. Oral medicine is more suitable for promotion. Patients don't have to go to the hospital for injection every day. Nowadays, with the improvement of the technology, there are a lot of drugs that used to be used in injections and now a lot of companies are gradually developing it into oral medicine.
According to the 2018 nature index, Cancer Centre of Sun Yat-Sen University ranked seventh among cancer centers worldwide.
6. Dinner party
We invited many virologists to have dinner together in order to have a deep conversation about virus. We started with their respective stories about their virus research. Then we talked about the current situation of oncolytic virus. Finally, we asked for their advice on our project.
Q1：At present, we are also committed to publicizing oncolytic virus to the public by spreading scientific knowledge and eliminating everyone's confusion, so that the public will not be afraid of the word "virus". What’s your views and Suggestions?
Professor Sun: That’s a good question. Our lab is also making oncolytic virus, but we call it “immunoenhancer”, which can avoid the word “virus” and emphasize the function of our product.
Q2: What are the current barriers to the development of oncolytic viruses
Professor Sun: So far, oncolytic viruses have been making no major breakthroughs for decades. A reason is that we often use protozoan viruses or only change one gene of the virus. However, such changes are very limited and cannot achieve the goal of curing tumors effectively. Secondly, there is no technical breakthrough to reconstruct the virus, and each of these oncolytic viruses has a great limitation for tumors. The other thing is that the limited market funds, funding for oncolytic viruses is very limited. Last but not the least, there is the dispersion of resources. Each oncolytic virus has very few people working on it, only a few teams or none, which greatly limits the breakthrough of oncolytic virus.
Q3: So where should the oncolytic virus go in the future?
Professor Chen: In my opinion, in the future, oncolytic virus should seek a major breakthrough in virus engineering. How to completely kill different kinds of tumor cells is a problem that oncolyic virus need to solve. Another key is how to get the virus to activate the body's anti-tumor immunity and enhance the body's own immune system's ability to kill tumor cells.
Dinner party with accomplished virologists
Professor Miao Xu, Professor Musheng Zeng, Professor Yerong Su, Professor Ren Sun, Professor Xinwen Chen, Professor Xi Zhong, Professor Pei Xu
7. TAICHI Emotion Stickers (TAICHIES)
To further promote our product, we had created a series of emotion stickers. Those lovely stickers named “TAICHIES” correspond to our group name “TAICHI”, which showed the concept of combination of M1 virus and prodrugs. We can put it on the Internet and spread it through WeChat and other social app so that we can arouse people’s interest in our products.
Click here to download the stickers
