Human Practices
Due to our team’s struggles with securing a lab space this year to conduct wet-lab work, we wanted to focus on a very important aspect of our project: Human Practices. As we assembled our team of students, a common theme among many of us was our desire to reflect on the social, ethical and moral implications of our work and how it applies in the real world. To achieve this, we spent much of our time engaging with the Ohio community and beyond, discussing not just about our project but about the more general goals and ideals of iGEM. We also ensured that our engagement was diverse from speaking with kids, patients and experts alike.
Colorectal cancer casts a significantly large shadow over the state of Ohio, impacting healthcare systems and the lives of its residents. Colorectal cancers accounted for 8.5% percent of all cancer related deaths in 2020, second only to Lung/Bronchus cancers (Ohio Annual Cancer Report 2023). Additionally, the majority of colorectal cancers are diagnosed at their regional stage, where they are still vulnerable to chemotherapy and radiation therapy (Colon and Rectum Cancer in Ohio 2021). Nevertheless, outcomes for colorectal cancer patients in Ohio are generally poor.
Discussions with colorectal cancer specialist Dr. Eric Miller at OSU’s The James Cancer Center revealed that 50% of patients with esophageal/colorectal cancers do not have a complete response to chemotherapy and will require surgery.
Statistics like these are especially concerning given the life-altering nature of many surgeries performed on late stage colorectal cancer patients. For example, many rectal cancers require large surgeries that leave patients with permanent ostomies, affecting their quality of life greatly.
These poor patient outcomes are largely due to the ineffectiveness of current drugs that aim to sensitize tumors to radiation and chemotherapy. For this reason, physicians in our community like Dr. Miller, as well as oncologists around the world, are in need of better therapies for their patients.
As a specific target to GI cancers, we plan on supplying healthcare providers with improved therapies. Since we use E. coli DH10B as the delivery vehicle for our therapeutic agents, tumor growths in the gastrointestinal tract would be the most ideal targets as the GI system is naturally home to a diverse and complex microenvironment.
Implementation of our project would involve several key steps. First, we hope to adopt a patient-centric approach by focusing on the specific needs of gastrointestinal cancer patients in the early stages of the disease. By targeting tumors in this region, we hope to provide a far less invasive option for treatment, reducing the physical and emotional burden on patients.
Going forward, to effectively integrate our project, rigorous research and development efforts would be needed, for example, to optimize our therapeutic agents and E. coli strains to interact well with the gut microbiome. Following this research, clinical trials would be needed in collaboration with healthcare providers and institutions to assess the safety of our therapeutic while strictly abiding by safety regulations.
If successful, our project has great potential to make a significant impact on the field of GI cancer treatment, offering a personalized and patient-friendly approach. This could eventually improve patient survival rates and lead to better overall outcomes for the world of healthcare. To get to this stage, our team took the initiative to begin having constructive engagement with our local and greater communities. For example, to better understand patient perspectives and the experiences with experts in the field, we researched gastrointestinal (GI) oncologists and reached out to individuals suffering with GI disorders. To help raise awareness about the goals of our project and the ways synthetic biology can be used to achieve them, we organized outreach events for kids and parents at The Center of Science and Industry (COSI), Boonshoft Museum of Discovery and WestFest at Ohio State (discussed in depth on our Education page).
To ensure that DiGI-T3 offered real insight and value to patients, we prioritized direct engagement with healthcare professionals and patients. Considering how universally relevant GI disease and cancer is in the lives of many, we recognized the importance of engaging with both healthcare professionals in the field of GI oncology and patients to ensure the impact of our project. Our overall approach to Integrated Human Practices involved two key components: professional outreach with physicians and conducting surveys among patients to gauge their interest in our project idea:
1) Professional Outreach
By engaging in professional outreach, our team ensured that our project aligned with the current needs and perspectives of healthcare professionals and stakeholders in the gastrointestinal field. This mainly involved presenting our project’s goals, methodologies, and potential impact, highlighting how it could contribute to advancements in research and patient care. We also actively sought out feedback and recommendations from experts, which helped us shape the direction of our project. Another key talking point was the potential implementation of our project going forward, and discussing ways that our idea could be brought to life.
2) Conducting Surveys
Understanding the needs and concerns of patients was equally important to our team. To achieve this, we conducted a series of surveys directed towards patients currently battling GI cancers and diseases to gather valuable insights. These anonymous surveys asked patients about the success of their treatments, their need for surgery, and their general interest in the implementation of our project.
Dr. Eric Miller is a radiation oncologist at the James Cancer Center who treats patients with gastrointestinal cancers. Dr. Miller, who has researched novel therapies that sensitive tumors to radiation treatment, helped our team brainstorm ways that our project could be implemented from bench to bedside. He specifically discussed potential delivery mechanisms that a developed medication could use to maximize efficiency and limit patient uncomfort. We also discussed the potential risks of using E. coli to treat diseases, particularly the concern of violent immune responses when targeting diseases outside the gut. The need for numerous early-phase studies to assess tolerance before clinical trials was emphasized, though conducting clinical trials on curative patient populations was deemed challenging due to risks. The focus then shifted to combining the proposed therapy with radiology, especially for esophageal and colorectal cancers, where the current treatment involves prolonged chemotherapy, radiation, and surgeries that can impact patient quality of life. Addressing the issue of patients not responding completely to chemotherapy was highlighted as a crucial goal. Lastly, there was a discussion about overcoming the negative stigma surrounding bacterial therapeutics, with an emphasis on patient awareness of our treatment's mechanism
Our team conducted two surveys; the first was specifically directed towards colorectal cancer patients and received 10 responses, while the second was directed towards patients of general GI disorders and received 67 responses. The questions were crafted in ways that paralleled our discussions with Dr. Miller. For example, we asked about the success of their treatment and their willingness to use E. coli to treat diseases. The collected data provided the team with great insight to the perspectives of those suffering from GI disorders in relation to our project. The results of these surveys are summarized below.
90% of the survey takers have been diagnosed with Colorectal cancer 1-2 treatments tried has been the most popular options among the survey takers- 0 (20%), 1 (40%), 2 (30%), 3 & 4 (0%), 5 (10%) While 66.7% had success with their treatments eradicating cancer, 33.3% haven’t had a successful experience 80% required surgery to treat their symptoms, suggesting struggles with responses to chemotherapy 60% of survey takers were open to taking an oral medication/enema/endoscopy and surgery involving a non-pathogenic strain of E.coli secreting nanobodies to target tumors Some of the common reasons people were against the idea were that current treatments are efficient and are sufficient or that it might be risky.
68.2% have been diagnosed with gastrointestinal disorder Most respondents have struggled with their condition for more than 10 years (39.4%) Many respondents have not used many treatments (0,1 or 2), however others have tried five or more (20%) On a scale of 1-5 (5 being best and 1 being worst), the majority of respondents rated the management of their symptoms at a 3 (43.9%). The majority of respondent (80.3%) would consider taking medications containing therapeutic non-pathogenic E. coli strains to help treat their conditions.
We found additional support of our project’s development in aspects other than human practices through discussions with other professionals. Their advice directly shaped the direction of our project and helped refine our approach:
Dr. Cammie Lesser at Harvard
Dr. Lesser is an Attending Physician at Massachusetts General Hospital and an Associate Professor of Medicine at Harvard Medical School. Dr. Lesser, who studies and tests the capabilities of Type III Secretion Systems, guided our team and provided valuable feedback during the initial conceptualization of our project. When brainstorming possible barriers to our idea, Dr. Lesser crucially informed us that folding and structure, not size, limits the capacity of T3SS to secrete proteins. With this information, the team amended its research strategy to focus on identifying and quantifying structural elements of potential therapeutic proteins to test. Dr. Lesser also commented on her success with secreting nanobodies via T3SS, and that the lack of structural components on these peptides likely make them efficient secretors. Following this discussion, our group decided to look into various diseases associated with gain-of-function mutations and search for nanobodies that target malfunctioning proteins. Additionally, Dr. Lesser discussed the difficulty of predicting secretion patterns given the limited data that is currently available. This inspired our team to begin brainstorming bioinformatics approaches to resolve this issue. Dr. Miller emphasized patient awareness of the treatment’s mechanism as there is a common negative stigma surrounding bacterial therapeutics. Because of this negative stigma, the team created a survey to identify how many people would be willing to take a medication containing non-pathogenic E. Coli that are capable of secreting nanobodies in the intestines to treat various GI conditions. Those results are in the GI Disorder Questionnaire section above.
Dr. Cheryl Immethun at Battelle
During our meeting with Dr. Cheryl Immethun, the following key points were discussed:
1) Project Scope: It was recommended to choose a protein that is relatively easy to achieve to account for the longer time wet lab work may take. Considering potential roadblocks and having resources available to address them was emphasized.
2) Communication and Visualization: It was suggested to replace words with pictures on the initial slide to make it more accessible and easily digestible for the audience. Additionally, the delivery method of the therapeutic proteins should be considered, avoiding disruptions to the gut microbiome if targeting the gut.
3) Organization and Time Management: Due to the time-consuming nature of building parts and the system, it was advised to stay organized and structured during the summer to ensure tasks are completed on time. Furthermore, initiating the Material Transfer Agreement (MTA) promptly and actively pursuing it was highlighted as an important step.
In summary, the discussion with Dr. Immethun emphasized the importance of choosing an achievable protein, considering potential challenges, and having resources in place. It was also suggested to enhance communication through visual aids, think about the delivery method, and maintain organization and timeliness. The prompt initiation of the MTA process was encouraged as well.
Dr. Shang-Tian Yang at The Ohio State University
Dr. Yang is a professor at The Ohio State University Food Science & Technology department and Chemical & Biomolecular Engineering department who specializes in bioprocessing research. Dr. Yang helped our team develop our secretion optimization model during its initial conceptualization. During our meeting, we discussed two potential model types: kinetics and degradation, focusing on the transport of proteins through the T3SS. Variables such as the location of the delivery vehicle and protein/size and shape were also considered when brainstorming secretion optimization, but it was concluded that there wasn’t a strong connection between these variables. We also discussed the need to consider the speed and potential degradation in their modeling efforts. From there we planned to develop a computational model to predict the optimized T3SS lead sequence, which would impact secretion efficiency. One crucial question raised was about the driving force behind T3SS, distinguishing between facilitated, active transport and passive mechanisms. Understanding this force is essential before proceeding with the modeling process. We also discussed the importance of the lead sequence and its impact on secretion and degradation. Folding of proteins after secretion was mentioned as a potential challenge. The team inquired about existing software, like AlphaFold, for predicting folding during secretion and its impact on the process.