Date of Award

2022

Document Type

Honors Thesis (Open Access)

Department

Colby College. Biology Dept.

Advisor(s)

Kevin P. Rice, PhD

Second Advisor

Andrea R. Tilden, PhD

Third Advisor

Rahul Sarpeshkar, PhD

Abstract

Cancer therapies over the last decade have promoted a growing interest in the manipulation of DNA damage and repair pathways due to its beneficial consequences on cancer cell viability. Simultaneously attacking genetic code with DNA-damaging chemotherapies while eliminating mechanisms of DNA repair – the protectors of our genome – has enormous therapeutic potential. Biological circuit engineering interfaces biochemistry and systems biology with electrical engineering analyses to accurately model and simulate biological pathways such as DNA damage and repair. Circuit models can also be used to identify weaknesses within pathways, highlighting the most efficient protein targets for drugs that aim to reduce cancer cell viability. This project explores the impact of two small molecules, cisplatin and spironolactone, on the fate of cancer cells. Cisplatin is a platinum-based chemotherapeutic agent that induces mono- and di-adducts on DNA, which distort its characteristic double-helix and hinder replication. Such lesions are primarily restored by a DNA repair pathway called Nucleotide Excision Repair (NER). Recent drug-repurposing studies have revealed spironolactone, a small molecule drug, as a potent and effective inhibitor of NER that, when combined with cisplatin, can significantly impact the viability of cancer cells. In this thesis, I create a biological circuit model of Cisplatin-induced DNA damage and spironolactone-mediated NER inhibition using Cadence, an electrical engineering analysis software. The model was derived with a combination of parameters from literature, laboratory experiments, and engineering insights. The tools employed in this project form the basis of a new and innovative instrument for drug design and crossing the threshold between authentic and synthetic biology.

Keywords

DNA, Cancer, Chemoresistance, Circuit Design, Feedback Systems, Tissue Culture

Download

Share

COinS