Building a diverse team means building an environment of inclusivity. We have two international students from Brazil and China, three first generation college students, and a wide array of cultural backgrounds and academic interests that are represented within our team. This allowed us to begin cultivating a space to produce project ideas from various perspectives and experiences. Our team’s diversity enabled us to have a more complex understanding of the issues within our local and global community and helped us brainstorm potential solutions. We believe that healthcare is a human right. This is what inspired our mission to pursue a project using the resources and privileges we have to make a global human impact among resource constrained communities. Ultimately, we reached a consensus using this mission statement to address the healthcare inequities present within Type II Diabetes Mellitus (T2D) treatment.
To understand the experiences of T2D patients on a global scale, we connected with endocrinologists, working practitioners, non-profit organizations (NGO), local organizations, and international communities. After learning subcutaneous administration of T2D medications host a variety of issues including needle supply, needle sterility, and bloodborne pathogens, we decided to produce Exendin-4 as an orally deliverable T2D medication [1]. Dr. Matt Sparke is a professor of politics at UC Santa Cruz, with an expertise in global health and wellness. We spoke with him to gain insight on diabetes at a global scale, focusing primarily on the socioeconomic aspects. He highlighted the issue of T2D transforming from an endemic disease into an epidemic. With the rise of fast food chains and a more sedentary lifestyle, susceptibility to T2D can manifest itself in regions previously thought to be low risk [2]. Before this discussion, our team had not considered the idea of diabetes being "transmissible", but this only reinforced our passion to tackle T2D.
After this conversation, we were eager to connect with international communities and learn about the different contexts in which inaccessible T2D treatment can manifest. We met with Lafia Wellness Initiatives, an NGO based in Benin, West Africa. Their mission is to promote preventative health care, education, and lifestyles while additionally providing support services to rural areas in West Africa. This includes providing T2D patients with a three month supply of insulin and teaching them how to properly and safely administer their own medication. Annette Oshin, the founder of Lafia Wellness Initiatives, emphasized the demand in rural areas for T2D treatment is huge, yet many people do not have the means to travel to pharmacies and hospitals for care.
After hearing numerous accounts of inequalities with T2D medications, our team decided to address this issue by conceptualizing a way to distribute safe, affordable, and accessible Ex-4. Once we came to this consensus, our outreach shifted to discussing a viable host with researchers that study non-native protein production in plant cells or bacteria. A plant host was particularly enticing as a biopharmaceutical that could express Ex-4; ideally one that could grow at a local clinic, thus reducing the cost and addressing the inaccessibility of current T2D medication. Organisms such as radishes, microalgae, and soybeans [6] were considered due to their bioencapsulation abilities and low glycemic indexes.
Our meeting with Micahel Burgis, a team member on the 2021 Marburg iGEM team, directed our host selection. Their team researched cell-free chloroplast systems from various plant models which inspired a way for us to use a plant model whilst bypassing the limiting factor of growth time. After speaking with Burgis, we were advised that producing Ex-4 in a faster model, such as yeast, would be an even better alternative for increasing the efficacy and feasibility of our project. Additionally, we realized a final plant model may require additional upkeep and resources as compared to yeast. Choosing a host free from these constraints is crucial for modeling an accessible biopharmaceutical. An easily growable host for production of Ex-4 allows for independence from traditional supply chains, thus empowering T2D patients to have control over their medication.
Following these conversations, we spoke to researchers at UC Santa Cruz to discuss alternative host models to use for our project. In particular, a meeting with Dr. Rohinton Kamakaka catalyzed our decision to work with the yeast S. cerevisiae. We discovered that S. cerevisiae is a model organism that accounts for 20% of biopharmaceutical production, including insulin [7]. S. cerevisiae can be grown as a starter culture and distributed as active dry yeast. We additionally discovered that S. cerevisiae has a doubling time of about 90 minutes and a versatile range of growing temperatures [8]. Due to its ability to be grown in a wide array of conditions, S. cervisiae became an attractive option for Ex-4 production, thus prompting a shift in our search for a host. For instance, dairy is a viable option for sustaining a yeast culture as it is widely accessible around the globe and has a relatively low glycemic index value [9]. S. cerevisiae proved to be an ideal host due to its combined ease of growth, GRAS status, and potential for oral delivery via bioencapsulation [10] [11].
After weeks of reading papers and hosting meetings with endocrinologists, biologists, and community outreach coordinators, we finally solidified our project: Helo. We seek to engineer stable expression of Ex-4 in S. cerevisiae as an affordable and accessible alternative to current T2D medication. To determine if this would be useful for T2D patients, we pitched our project proposal to stakeholders such as endocrinologist Dr. Tércio Rocha from Brazil.
Dr. Rocha informed us that GLP-1 RAs can cost up to $200 (USD) in Brazil with the additional context of many patients' monthly salary being around $250 (USD). His portrayal of people’s access to T2D medications and the unreasonable cost of life-saving therapeutics strengthened our goal to make Helo as cost-effective as possible.
We were eager to see how Helo could theoretically be implemented within the organizations that work directly with T2D we spoke to previously. We first reconnected with Lafia Wellness Initiatives to assess if Helo, once fully developed, could be incorporated into their program. Their response was encouraging. Oshin informed us that FDA approval and clinical trials before implementation would be essential, but a product like Helo would help the lives of many. We then pitched our final project proposal to medical professionals who have extensive experience with T2D: Dr. Lawrence DeGhetaldi and Dr. David Ghilarducci. We also followed up with Dr. Rayhan Lal to get feedback on the feasibility and useability of Helo. In our meeting with him, we discussed bioavailability of potential non-subcutaneous delivery methods including buccal, oral, and dermal delivery. We additionally discussed dairy as a growth medium for S. cerevisiae producing Ex-4 and the wide flexibility of Ex-4 dosage, given it is nearly impossible to overdose on [12]. Each of these discussions confirmed that Helo has authentic motivations and solutions.
Dr. Patricia Wu informed us about the effects of taking GLP-1 RAs, including their impact on stomach emptying, appetite, and blood glucose regulation. Dr. Wu additionally mentioned GLP-1 RAs are typically short acting and can be degraded easily. We also connected with Dr. Samuel Pine, a biotechnology professional specializing in immunology, and Dr. Sebastian Bernales, a cell biologist and biotechnology entrepreneur, to get feedback from professionals in the industry. While both of them were impressed with Helo, they questioned the bioavailability of orally administered Ex-4 in S. cerevisiae as compared to injectables. This prompted us to research mechanisms by which we can improve the bioavailability of Ex-4 as an orally administered T2D therapeutic. An elastin-based polypeptide half-life extender was added to the Ex-4 gene insert for S. cerevisiae in response to this concern.
From the beginning of the summer, we understood the significance of collaborative dialogue and its impact on our project. Input from individuals around the world altered our path to success more than once, and played an essential role in guiding us towards our final implementation. It is Helo's priority to make a positive impact on improving accessibility of diabetes therapeutics while upholding our core belief: healthcare is a human right.