Designing the Optimal PDAC Tumor Microenvironment; Balancing Ethical and Societal Responsibilities: CRISPR

Cancer is currently one of the world’s biggest health challenges. Cancer is distinguished by the growth and spread of malignant cells that can occur in almost any tissue or organ, causing a variety of distinct cancer types. In the ever-changing landscape of healthcare, there is a need to evolve cancer research and treatment. While traditional methods have yielded great results, cancer is constantly mutating and getting more complex. The intricacy of cancer allows these malignant cells to not only mutate but also interact and manipulate its surrounding environment including other cell types such as immune cells. Biotechnology enables the development of innovative therapies, vaccines, and personalized medicine, which have revolutionized modern medicine.
Hydrogels are a recent new biotechnology that researchers are using to model the tumor microenvironment and drive cancer research. Hydrogels are great for modeling the tumor microenvironment and cancer progression due to their unique characteristics such as biocompatibility, tunable properties, and high-water content. My technical project focuses on designing a hydrogel microenvironment capable of modeling the tumor microenvironment of pancreatic adenocarcinoma (PDAC), capturing the effects cancer-associated fibroblasts (CAFs) have on their environment.
However, while the rise in biotechnology helps to progress modern medicine, it also raises questions about the ethical and societal considerations that surround biotechnology. CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), a revolutionary gene editing technology has transformed the field of genetics, offering unprecedented opportunities to treat diseases at the genetic root. However, others have also used gene editing for human enhancement purposes such as cosmetic enhancements, genetic modifications, or neurostimulation. My STS research question asks: What are the ethical and societal responsibilities of healthcare systems in regulating the use of CRISPR for human enhancement versus therapy, and how can these responsibilities be balanced to ensure equitable, just, and responsible application of gene editing technologies?
To fully understand the role cancer-associated fibroblasts play in pancreatic adenocarcinoma, I must characterize CAF subtypes and their enzymatic secretion in a 2D and 3D environment. In PDAC, there are three subtypes of cancer-associated fibroblasts: myofibroblasts, inflammatory CAFs, and antigen presenting CAFs. I will utilize immunostaining techniques where I stain for biomarkers unique to each subtype to distinguish between subtypes. CAFs secrete enzymes called matrix metalloproteinases to degrade and remodel the extracellular matrix. I will use zymography, an enzyme detection technique to detect both the pro- and active forms of MMP-9 and MMP-2, the two metalloproteinases that are associated with tumor progression. Next, I will assess CAF behavior in a 3D culture model of the tumor microenvironment. CAFs secrete extracellular matrix components to remodel the extracellular matrix, creating a stiffer environment. I will encapsulate CAFs in hydrogels of varying stiffness, representing healthy pancreas and stages of pancreatic cancer, to analyze CAF matrix production, soluble factor secretion, proliferation, and migration in the various hydrogel environments. I will co-culture CAFs with both human umbilical vein endothelial cells (HUVECs) and pancreatic cancer cells in both 2D and 3D environments to study their interactions and on the ability of CAFs to impact angiogenesis and cancer cell proliferation and migration. By achieving these aims, I will be able to understand how CAFs play a role in tumor progression and growth.
What are the ethical and societal responsibilities of healthcare systems in regulating the use of CRISPR for human enhancement versus therapy, and how can these responsibilities be balanced to ensure equitable, just, and responsible application of gene editing technologies? First, we must discuss what ethical and societal responsibilities current healthcare systems must abide by when making decisions about the use of CRISPR to ensure CRISPR is used in a manner that is just, fair, and avoids broader societal harm. CRISPR regulatory frameworks, guidelines, and policies will be analyzed to understand how healthcare systems interpret these regulations to monitor, control, and guide the application of CRISPR. Through analysis of case studies using CRISPR in human enhancement purposes versus therapeutic purposes, we can begin to understand the clear distinction between the two uses and the unlikely similarities they may share. Lastly, we will discuss how healthcare systems can manage the competing demands of ensuring fairness, maintaining justice, and being responsible in the application of CRISPR. To gather evidence, I will conduct a literature review using peer reviewed journal articles, policy documents, regulatory frameworks, public opinion polls and surveys and op-eds. I will review peer-reviewed journal articles on CRISPR, focusing on both therapeutic and enhancement uses. I will use policy documents and regulatory framework to analyze the regulation of gene editing technology. I will use op-eds and public opinion polls and surveys to analyze public perception on CRISPR. To ensure my evidence is authoritative, I will prioritize primary and secondary sources, peer-reviewed journals, and be cautious of any sources with conflicts of interests.
Studying tumor progression allows for a deeper understanding of how PDAC grows, identifying new methods to catch PDAC at an earlier, treatable stage. The study of the tumor microenvironment in a 3D system gives us a more realistic and detailed model to analyze and inspect how every cell type, growth factor, or signaling pathway works together to promote tumor progression. To achieve this goal, I characterized the enzymatic expression of CAFs in a 2D and 3D environment and assessed CAF behavior in a 3D culture model of the tumor microenvironment.
The ethical and societal responsibilities of healthcare systems in regulating the use of CRISPR for human enhancement versus therapy are multifaceted and require careful consideration of both the potential benefits and risks of gene editing technologies. There are many ethical and societal considerations to take into account such as safety and unintended outcomes, naturalness, access, justice, and human rights and decision-making (“playing God”). Healthcare systems must regulate CRISPR in a precise way that prevents the creation of a society divided by genetic privilege, while also ensuring access to the technology for those with medical needs and in vulnerable conditions. Regulation should be designed to reflect the current societal majority and avoid policies that disproportionately benefit certain groups. Together, these projects reflect dual engagement with both the material and moral dimensions of biotechnology innovation.

School of Engineering and Applied Science

Bachelor of Science in Biomedical Engineering

Technical Advisor: Lakeshia Taite

STS Advisor: Kent Wayland