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Team:PYMS GZ China/Human Practices


Human Practices

As a team, we knew that we wanted to help the greater good of humanity, not just focus our project on something that affects a niche group. As scientists, our job is to make a direct positive, significant impact on the community as a whole. This led us to think of conducting our research on COVID-19. Before beginning in this direction, we decided to conduct a survey to gauge the public’s view on COVID-19. Surveying 252 people in our communities, ages ranging from 10 to 60, we saw that the majority of the people believed COVID-19 is dangerous, if not very or extremely dangerous. In our survey, we also saw that people are taking extreme caution in keeping themselves safe--social distancing and wearing masks.

Our engagement with the community confirmed our project idea of researching COVID-19. COVID-19 has affected everyone; it does not have one target. Across the world, people of all backgrounds have been infected and millions of lives have been lost. We felt that researching COVID-19 fulfilled our mission of bettering humanity.

Now knowing that we wanted to focus our project on COVID-19 due to its impact on the world and in our local communities, we also knew we needed to consider the dangers. Human practices were integral to our project because we had to continuously think about the safety and impact of our project on the world; we wanted to conduct research relating to the virus without possibly causing an outbreak in the process. Our top priority was keeping our Wet Lab Team and those assisting us in our project safe. Upon conducting our own research, we saw that research on COVID-19 is done through isolating SARS-CoV-2. This was not an option for us because we believed it was very dangerous and infectious, along with the fact that we are prohibited from using the live virus in our project for iGEM.

With this in mind, we engineered a pseudovirus containing the S protein present in SARS-CoV-2, but missing the virulent components that cause a typical virus to replicate. Pseudoviruses are commonly used in scientific research, and therefore can replicate once, which could be handled in the lab. In this way, we could research SARS-CoV-2 while keeping ourselves and the rest of the community safe.

The first idea that came to our minds was creating a vaccine. Moreover, we had to consider the ethical and moral dilemmas of creating a vaccine. Before undergoing vaccine development, we had to analyze if the benefits outweigh the risks. In this case, COVID-19 has become a world crisis, infecting millions and killing hundreds of thousands of people, so a vaccine would outweigh the harm that COVID-19 poses. Creating a vaccine in the iGEM competition would mean infecting animals with the live virus and then our vaccine, as we are not allowed to test on humans. This raises ethical concerns about animal well-being because the virus could pose a large threat to animals, possibly leading to death if our vaccine is not viable. Before testing on animals, we would need to consider all treatments and be sure that the vaccine we created was the safest option. Eventually, our vaccine would need to be tested in human trials, which puts lives at risk, since we would infect the participants with the virus, according to the World Health Organization. In addition, as coronavirus is very infectious, participants need to be carefully monitored, along with those that have been in contact with them. We would not want to cause the participants in our trials to infect other people. In addition, we had to consider the safety of our Wet Lab Team who would be conducting experiments. Furthermore, those that are in contact with our Wet Lab team and the general public could be exposed.

Knowing the time period we had to create a vaccine, we did not want to test a vaccine on an animal unless we were concretely certain of the effects and results. We did not want to test anything on an animal unless we had enough evidence and research that our created vaccine would have a good chance of a positive outcome. This led us to the conclusion that creating a vaccine would not be feasible in the amount of time we had.

Biosecurity was a driving force that influenced our project. When designing our experiment, we wanted to create a procedure that would ensure the safety of our teammates and anyone who would become exposed to our experimentation. Therefore, we came to the conclusion that the best option was using our engineered pseudovirus to test the infectivity of two strains: the dominant strain and the original strain of SARS-CoV-2.We incorporated the pseudovirus that contains the Spike protein into our design since the virus is not harmful to the body since it lacks the genetic machinery to reproduce and further infect. In this way, we would be helping the community by providing knowledge that would help guide scientists’ research regarding creating a vaccine. Also, we would create a procedure that could be used to test the infectivity of other viruses. Further, we would be keeping the community safe as we are not harming any person or animal in the process.

References
  1. Maderer, Jason. The Ethics of Developing COVID-19 Treatments and Vaccination - News -Carnegie Mellon University, Carnegie Mellon University , 7 Apr. 2020, www.cmu.edu/news/stories/archives/2020/april/ethics-vaccination.html.
  2. Wellcome , et al. “Safety First: How to Run a Covid-19 Vaccine Clinical Trial.” Wellcome, 11 Sept. 2020, wellcome.org/news/safety-first-how-run-covid-19-vaccine-clinical-trial.
  3. World Health Organization. Key criteria for the ethical acceptability of COVID-19 human challenge studies. No. WHO/2019-nCoV/Ethics_criteria/2020.1. World Health Organization, 2020, https://wellcome.org/news/safety-first-how-run-covid-19-vaccine-clinical-trial
Integrated Human Practices

We interviewed doctors working in infectious disease, virology, epidemiology, and similar fields to discuss our project ideas and gain insight into COVID-19.

Interview with Dr. Camille Kotton

Background

Dr. Kotton is an infectious disease specialist at the Massachusetts General Hospital in Boston. She is a clinical director at the hospital, and she is involved in transplant surgeries as well as in the study of immunocompromised infectious diseases. She completed her education at the University of Chicago Pritzker School of Medicine, she completed her residency at the Hospital of the University of Pennsylvania, and her fellowship at Massachusetts General Hospital. She is certified in the study infectious disease by the American Board of Internal Medicine.

Summary

While talking to Dr. Kotton, we learned about how busy her work is currently, and how the ongoing pandemic is affecting patients and studies taking place in the hospital she is working at. She explained that the majority of her patients are the elderly, and the number of patients was smaller as the age got younger. She also explained how the virus is affecting a variety of body systems, but mainly it causes damage to the lungs and kidneys. Currently, hospitals are using two main treatments as well as antibiotics to treat people with severe symptoms. This then segwayed into her explaining how she thinks our idea of creating a universal vaccine is a great one, but one that is extremely hard to execute. This was helpful for our team because her statement on the difficulty of creating a universal vaccine helped prompt our team to take our project in another direction. She then spoke about current facilities that are fighting COVID-19, and how the future might look. It was very interesting and extremely helpful to hear her explain two perspectives of what our future may look like, with and without a vaccine.

Takeaway

Our interview with Dr. Kotton was insightful because it prompted us to begin thinking of projects outside of creating a vaccine. As a team, we began brainstorming other research topics related to COVID-19 that would help the community, eventually leading us towards creating a pseudovirus general assay system instead after conducting more interviews.

Interview with Dr. Alice Huang

Background

Dr. Huang is currently a professor at CalTech, in the Division of Biology and Biological Engineering. She completed her education at Johns Hopkins University and Harvard University. She was also the Dean of NYU before teaching at NYU. She is known for her work in the fields of virology, microbiology, and immunology. This includes her work surrounding RNA and DNA enveloped viruses such as leukemia viruses, herpes viruses, and human immunodeficiency virus.

Summary

Our interview with Dr. Huang was essential in guiding our project. We gained more insight about ways in which scientists are working to combat the new coronavirus and how SARS-CoV-2 affects the body in so many different ways. This was extremely helpful because the information she relayed to us allowed our team to understand how the virus targets the cells and gave us insight on how we can target the virus. She spoke a lot about how the immune system combats SARS-CoV-2 and other viral infections. She also mentioned how to test the infectivity of the strain, and how this can affect who is asymptomatic, who is slightly symptomatic, and who is severely symptomatic. This segwayed into a very important topic about treating symptoms and different ways to aid the body in fighting off the infection. We learned, in depth, about pseudoviruses, and what our team would need to do in order to successfully make one. Also, we learned about how the infectivity of viruses are measured. We learned that virologists indirectly measure the infectivity of viruses by injecting the virus into animals. They do this by measuring the amount of virus they injected into the animals and seeing how much of the virus it will take for 50 percent of the animals to die. Another way virologists indirectly measure the virus, Dr. Huang explained to us, is by taking cells in a culture and making a monolayer out of them, and doing a plaque assay with the virus. Overall, hearing from Dr. Huang was very insightful as she has a lot of experience and knowledge in the field.

Takeaway

Understanding the methods in which virologists measure the infectivity of viruses was crucial in directing our project. We learned that there is currently no direct way of measuring the infectivity, and we sought to pioneer a way to directly measure the infectivity of different strains of SARS-CoV-2. This led us to come up with the idea of creating a pseudovirus general assay platform.

Interview with Dr. Meghan May

Background

Dr. May is currently a professor at the University of New England College of Osteopathic Medicine. She is an expert in microbiology and infectious diseases. She is currently researching measuring evolutionary changes to identify pathogenic/clinical targets of emerging viruses and diseases, such as Zika, SARS-CoV-2, and the Crimean-Congo Hemorrhagic Fever virus. She has published work in over 40 publications, and her work is recognized at national and international gatherings.

Summary

Our interview with Dr. May gave me a lot of insight into the pandemic, including in depth analysis of how the new coronavirus affects different people and how scientists are trying to combat it. She talked in depth about patterns she saw in the infected patients, giving us a deeper understanding on SARS-CoV-2 and its relation to immunity. She noticed inflammatory markers were usually found in the blood of patients who were severely affected, as well as how they ended up in that state through a cytokine storm (over amplified immune response that can damage your own tissue instead of the virus). She discussed some good ideas regarding how SARS-CoV-2 affects different organs in the body, mostly focusing on the virus’s Spike protein and types of tissues it can interact with. We talked about the makeup and differences in SARS-CoV-2 in comparison to SARS-CoV, particularly the RGD motif. Then, we talked in detail about three important treatments that work on different levels. Dr. May explained how we could block the binding with a molecule that physically interrupts the binding or tricks the Spike protein into thinking it has already binded. To tag the virus, Dr. May introduced multiple interesting methods, such as sphere imaging. She also mentioned ways to visualize a virus through a recombinant viral strain, where a very small fluorescent protein would be placed inside a capsule. Dr. May then talked about how the animal system would be great for testing infectivity, but there are complications to take into consideration, such as the ratio of viruses to cells scaled in a living organism. In order to test the infectivity of the virus, we need the right tools. Without the animal model, it’s difficult to pinpoint how and where a person contracted their infection. This information about the methods helped us with our research and experimental procedure. Overall, this interview with Dr. May gave us a better understanding of how the virus works, and it was an honor to learn from such a renowned professor.

Takeaway

The interview with Dr. May was important in guiding our project because the information she provided us about the methods of measuring infectivity aligned with what we learned from our interview with Dr. Huang. Dr. May informed us that an animal model is the best and current strategy to test the infectivity of different strains of SARS-Cov-2 , which aligns with Dr. Huang’s strategy. This interview with Dr. May further confirmed our project direction in creating a pseudovirus general assay system to directly measure the infectivity of different strains.

Interview with Dr. Xiaogang Bi

Background

Dr. Xiaogang Bi is the Director and Deputy Chief Physician of the Comprehensive ICU of Third Affiliated Hospital of Sun Yat-sen University Lingnan Hospital.

Summary

Our interview with Dr. Bi was helpful and clarifying. We gained more insight on the fundamental workings and impacts SARS-CoV-2 has on our bodies. Dr. Bi explained how, despite the fact that the lungs are most affected, SARS-CoV-2 can affect many body parts. He then explained the three main factors that would onset symptoms: our body’s immune system, the virus itself, and a possible intervention factor. Dr. Bi told us about the main treatments being used, including symptomatic treatment, antiviral therapy, immunotherapy and anti-inflammatory therapy. He suggested blocking the binding with an antiviral drug, similar to anti-infective drugs. An issue with creating the pseudovirus is that the virus is constantly mutating. Finding a solution to this problem is key to a detection system. In order to detect infectivity, Dr. Bi suggested animal experiments or genetic testing, rather than clinical testing. He informed us that researchers track which strain is the most dangerous (as the virus is constantly mutating) first through clinical observations, then laboratory observation, animal inoculation, understanding the pathogenicity of the virus and then understanding the risk.

Takeaway

Dr. Bi opened our eyes to methods of identifying infectivity. The method he suggested was through animal testing or genetic. Speaking with him, he supported the relevance and need for our project. The information we learned from Dr. Bi’s interview agreed with what we learned from our interviews with Dr. May and Dr. Huang, further confirming our goal of creating a pseudovirus general assay system to test the infectivity of different strains. Before our interview with Dr. Bi, we did not know how to approach the method of tracking the infectivity of strains through clinical observations. With this in mind, we knew that our general assay platform would be a breakthrough in the scientific community since our system would directly measure the infectivity of all SARS-CoV-2 strains.

Interview with Dr. Guoli Lin

Background

Dr. Lin is the deputy chief physician, presiding over and participating in a number of national and provincial scientific research projects. She has published more than 30 papers related to hepatitis and infectious diseases. Dr. Lin graduated from Zhongshan Medical University with a clinical major in 1999. After graduation, she was engaged in first-line clinical work in the Department of Infectious Diseases and is an expert in diagnosis and treatment of viral hepatitis, cirrhosis, liver failure, especially hepatitis B and C. She also has rich clinical experience in other liver diseases (such as alcoholic liver disease, genetic metabolic liver disease, drug-induced liver disease, etc.) and common infectious diseases, and her development direction is the long-term cohort follow-up study of chronic hepatitis B and hepatitis C.

Summary

At the beginning of the interview, we learned about how hospitals in Guangzhou are handling the pandemic, and what the situation looks like currently. We were told that clinics and hospitals were open to treat people, and different levels of employees throughout the hospital were tasked in trying to solve this unprecedented problem. They explained how the situation in Guangzhou is now under control and has been handled very well. We now know that due to the use of specialized hospitals used to treat coronary pneumonia, the situation is under control. Then, we began to talk about how the virus affects different aspects of our bodies. We learned how it targets many organs, but the main ones include the heart, lungs, and nervous system. Something new that we learned was that generally asymptomatic patients are not as infectious as the ones that show symptoms. We spoke about treatments for these symptoms that have proven successful over this pandemic. These include interferon, nebulization therapy, thymosin, ribavirin, immunoglobulin, plasma exchange, and more. We then transitioned into the molecular biology behind the virus. They gave us useful insight on the anatomy of RBD spike protein and how it interacts with ACE2 cells. We also discussed different markers such as luciferase and GDF protein.

Takeaway

Dr. Lin's interview prompted us to include a luciferase plasmid in our pseudovirus, allowing us to detect the value of chemical luminescence using a fluorescence microscope to determine the infection efficiency of SARS-CoV-2. Their method to test infectivity is combining the patient's clinical symptoms, laboratory indicators, whether there is an underlying disease, and comparing the gene sequence of the obtained virus strain with the nucleic acid sequence of the existing COVID-19 to determine whether it is a high-risk virus strain. This strategy is not completely accurate and motivated us to create a pseudovirus assay system to develop a concrete system that can be used to test infectivity.

Interview with Dr. Peng

Background

Dr. Peng is the executive director of the Clinical Medical Research Center and the director of the "COVID-19 Isolation Ward" of the Third Affiliated Hospital of Sun Yat-sen University. He is deputy leader of the Liver Failure and Artificial Liver Group and Infectious Disease Branch, Deputy Chairman of the Youth Committee of the Infectious Diseases Branch, a Young member of the Infectious Diseases Branch, and a Member of the Medical Virology Branch of the Chinese Medical Association. Dr. Peng is also a Member of the Guangdong Medical Association Standing Committee of Infectious Diseases Branch and Member of the Guangdong Preventive Medical Association Standing Committee of Infectious Diseases Branch.

Summary

This interview was very helpful as Dr. Peng explained many concepts on a molecular level, and was also eye-opening to how other countries are dealing with COVID-19. At the hospital Dr. Peng is working at and in China in general, the disease is well-controlled. Despite there still being much work regarding observation, treatment, and follow-up of patients, Dr. Peng said that in the long term, SARS-CoV-2 will not pose a threat to the Chinese medical and health systems. We learned that COVID-19 can be found in four types of specimens: peripheral blood, throat swab, anal swab and urine, and that the amount of virus in a specimen is not necessarily parallel to a patient’s condition. We learned about how RBD spike protein of SARS-CoV-2 could potentially be used to create a vaccine that blocks binding and how some Chinese doctors and researchers are testing the effectiveness of their vaccines. We learned that there is still much work to be done in regards to testing the infectivity of viruses. Moreover, Dr. Peng spoke to us about pseudoviruses, including what they are/could be used for and what types we can consider. We also learned a lot about SARS-CoV-2’s mutations. Dr. Peng informed us that in the past, the entire process of SARS outbreaks has always been brief, yet the current pandemic is still ongoing after months. He described how different kinds of mutations may be factors in how SARS-CoV-2 has maintained its prevalence. Overall, speaking with Dr. Peng was extremely insightful and provided a lot of knowledge essential to guiding our project.

Takeaway

Understanding pseudoviruses and their potential was crucial in directing our project as it allowed us a method to safely conduct research on SARS-CoV-2. Furthermore, he guided us to decide which pseudoviruses would be feasible in our project. Another critical concept was how infectivity of viruses is tested. Through this interview, we learned that there is still no efficient or 100% effective way of testing infectivity of different strains of SARS-CoV-2. This gave us another motive to create the pseudovirus general assay system.

Interview with Dr. Xinhua Li

Background

Dr. Xinhua Li is the Director and Deputy Chief Physician of the First Ward, Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University.

Summary

In this interview, we spoke about the virus and his thoughts on the current situation of the world. Dr. Li touched on how the virus compares to the SARS outbreak in 2003, and this was extremely interesting to hear. He explained how in the early and middle stages of this pandemic, social distancing, masks, and centralized treatments are way more effective than the vaccines and newest technologies; the performance of the United States and China throughout this pandemic show that. He also voiced that a vaccine does take a huge amount of tests, procedures, and trials before it even gets distributed to the public. Even then, we don’t know if it will be successful since it is on such a large scale. We then went on to discuss his research in Wuhan, China, where he was experimenting on how long COVID-19 antibodies can last in the human body. Since China managed the pandemic very well, his research was unable to continue. We then moved on to talk about the molecular biology behind SARS-CoV-2. He spoke in-depth about how the virus targets so many different organs in the body through the RBD-Spike protein binding to the ACE2 receptor, which is on many organs in the body. Dr. Li stated that the respiratory tract, and therefore the lungs, are by far the most affected area of the body by COVID-19. He also explained to me that some individuals with COVID-19 are asymptomatic due to the fact that some people’s ACE2 receptors do not bind with the virus, and therefore the virus is unable to infect the person. It can also depend on the number of viruses that entered the body in the first place. We then transferred into the realm of treatment. Dr. Li explained that the treatment for COVID-19 is currently symptom control and support. He mentioned many specific types of treatments being used. When we spoke about blocking the binding of receptors when the virus enters the body, he responded that it is manageable, but would have to be done in the early stages of infection. When we spoke about keeping track of the most dangerous strains, he said it is something that is extremely difficult to do because we usually judge after the fact.

Takeaway

Dr Li’s interview was important during our brainstorming phase in deciding what direction to take in our COVID-19 research. He gave us critical information about the binding affinity of ACE2 and RBD that became important in how we would identify the infectivity of different strains of SARS-CoV-2. Learning more about this relationship, it inspired us to implement mammalian cells expressing ACE2 receptors that our pseudovirus can bind to in our protocol.