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Gabby Bulliard
Author: Gabrielle Bulliard | Major: Biomedical Engineering
Over the past year, I have been working with a group of fellow biomedical engineers in an initiative called the Alpha Research Program, developed by the local student chapter of the Biomedical Engineering Society (BMES). The program allows undergraduate students to earn hands-on experience with biomedical technology and research without the large time commitment that many labs in our department require. Under the guidance of Prof. Leonard Harris, my lab partners and I have been constructing a computational model of the WNT3 signaling pathway in breast, lung, and prostate cancer cells that have metastasized to the bone. This semester we focused on fine tuning the model and making its execution more accurate with respect to the biology of the pathway.
The WNT3 pathway drives the production of multiple proteins in tumor cells, including parathyroid hormone-related protein (PTHrP), which drive tumor-induced bone disease (TIBD), an umbrella term for a condition that often arises after tumors establish in the bone, characterized by increased fractures, spinal compression, pain, bone marrow dysfunction, and hypercalcemia. Many labs are trying to develop a comprehensive treatment for TIBD that kills tumor cells and prevents bone destruction but are hindered by the complexity of the underlying signaling pathways activated during tumor establishment and metastasis, including WNT3. Our computational model could assist researchers in developing improved treatments by identifying novel molecular targets and predicting the response to different drugs/treatments.
Our aim this semester was to rewrite and expand the code for the “destruction complex” portion of our model. The destruction complex is a multi-protein macromolecule that sequesters β-catenin, the main protein driving the production of PTHrP, and allows for its ubiquitination and subsequent degradation. During the summer of 2021, we created a skeleton model of the destruction complex that amounted to a few lines of code in our main model. This skeleton model was not meant to be the final product and we ended up rewriting the entire sub-model. We had many issues with the initial draft version of the destruction complex model, including the creation of an unintended infinite loop. Our model creates “species” from a set of reaction “rules,” which we encode to describe interactions between different proteins and protein complexes. The reaction rules apply to specific locations of the proteins under specific conditions (known as the reaction “context”), which we define. However, in the skeleton model many of the reaction rules were underdefined and, thus, happened under conditions that were not biologically realistic. Specifically, many species were continuing to react when they should not have been able to, had the model been correctly defined. This led to our code running in an infinite loop and producing thousands more protein complexes and reactions than there should have been. Thus, we had to edit our model one line at a time to correctly define the reaction rules so that proteins bonded in the correct places and under the appropriate conditions.
Our next goal is to merge the new destruction complex code into the main model. Once the new model is fully implemented and validated, we will delete the old destruction complex reaction rules and replace them with the new ones. We also plan to meet virtually and in person with Prof. Julie Rhoades and her lab at Vanderbilt University to discuss the current version of the WNT3 model. Prof. Rhoades is an experimental collaborator of Prof. Harris and they are currently working together with Prof. Karthik Nayani of the Dept. of Chemical Engineering here at UA on an NIH/NCI grant application on TIBD. Getting to see first-hand how grant applications are put together will be exciting and a great learning experience.