Elucidating Plectin Specific Pathways to Develop Novel Pancreatic Cancer Therapies; Power, Profit, and Access: Ethical and Social Implications of Biotechnologies in Healthcare

Sociotechnical Synthesis

Technical Project Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a 5-year survival rate of 13%. Despite decades of research, there have been no significant improvements in overall prognosis for PDAC patients in over 40 years, accentuating the need for novel therapies. Plectin, a cytoskeletal linker protein, has been identified as a novel cancer-specific target as it is mislocalized to the cell surface (herein described as CSP) in cancer. Loss-of-function studies have implicated CSP as a pro-tumorigenic regulator of cancer cell proliferation, migration, and invasion in PDAC. While CSP has been identified as a tumorigenic factor, the mechanism of plectin-induced cancer remains elusive. The primary goal of this project was to understand the molecular mechanism of plectin and its role in tumorigenesis as well as potential resistance mechanisms to plectin targeted drugs. We utilized CRISPR-Cas9 to develop a tetracycline-inducible complete knockout (KO) of plectin in human PDAC cell lines (L3.6, Panc1, and MIA PACA) to examine real-time mechanisms across stages of plectin-KO. PDAC cell lines contained a negative control group (HRPT-KO) and a plectin-KO group. Short hairpin RNA was used in preliminary experiments to knockout HPRT and plectin in PDAC cell lines. These lysates were analyzed by western blot to assess the expression of key regulators of the cell cycle and signaling pathways, p21, cyclin D1, and phosphorylated ERK1/2. Initial western blots analyzing the CRISPR/Cas9 KO cell lines suggested refinement for tetracycline treatment and gave preliminary insight into the mechanism of plectin-mediated proliferation.

STS Project Abstract
Over the past century, biotechnologies have had a big impact on the healthcare industry, leading to innovative drugs, tools, and treatments to improve patient outcomes. Notably, CRISPR/Cas9, a gene editing tool, has been used to increase the efficacy of an emerging cancer therapy, Chimeric antigen receptor T (CAR-T) cell therapy, showcasing the potential of biotechnologies to dramatically improve human well-being. However, the commercialization of biotechnologies like CAR-T cell therapy also have the potential to dramatically widen existing social inequalities when you look at the intersection between STEM, the economy, and class. This leads us into insights about my research question: how does the commercialization of biotechnologies in the biomedical industry challenge social and ethical frameworks related to human health access? To explore this research question, I use a literature analysis and social-political framing to explore the intersection of power structures. CAR-T cell therapy displays the financial barriers to healthcare access and the commercialization of life-saving treatments, the ImClone scandal illustrates failures in corporate governance and ethical decision-making in the biotech industry, and antiretroviral drugs for HIV/AIDS highlights how intellectual property laws restrict global access to essential medicines. Langdon Winner’s technological politics framework and Faden and Powers’ justice framework are also used to help analyze these case studies. Expanding ethical oversight mechanisms and implementing corporate social responsibility (CSR) frameworks can help biotech companies align profit motives with public health objectives. As this can be challenging, future research should focus on creating universally accepted metrics to evaluate the long-term impacts of CSR initiatives.

Intersection of Projects
My technical project relies on the use of the CRISPR/Cas9 gene editing tool to design tetracycline-inducible complete knockout (KO) of plectin in human PDAC cell lines. These cell lines will allow us to understand the mechanisms of development and progression of PDAC, laying the groundwork in which novel cancer therapies can be developed in the hopes of improving patient outcomes. Therefore, my technical project is concerned with scientific advancement and the development of novel biotechnologies. Of course, with the development of novel cancer therapies, they will eventually become commercialized. This leads to the topic of discussion in my STS project. My STS project is concerned with the social and ethical implications of scientific advancements and the commercialization of biotechnologies. In this project, I critically analyze how the commercialization of biotechnologies, such as CAR-T cell therapy, a novel cancer therapy, may exacerbate existing inequalities in healthcare access. In this way, my STS project builds directly on my technical project and addresses the social aspects of my technical work. My STS project also goes a step further by offering tools that could guide future clinical translational research such as the work from my technical project. Together, my technical and STS projects provide a comprehensive view of the biomedical industry spanning from the research required to develop biotechnologies, and the effects of the commercialization of these biotechnologies.

School of Engineering and Applied Science

Bachelor of Science in Biomedical Engineering

Technical Advisor: Kimberly Kelly

STS Advisor: Joshua Earle

Technical Team Members: Zachary Jung