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The problem of controlled bacterial adhesion spans biology and we mean to solve it! Our approach and | The problem of controlled bacterial adhesion spans biology and we mean to solve it! Our approach and | ||
Revision as of 11:30, 18 September 2015
BactoGrip: Where we began
Colon cancer is the second leading cause of cancer death in the United States. Each year, almost 140,000 people are diagnosed with colon cancer, and 50,000 people die from the disease. Diagnosis and treatment often require invasive procedures, including colonoscopies and surgery. Less invasive treatments such as chemotherapy cause unpleasant side effects. We turn to synthetic biology to develop a better colon cancer therapy. An ideal cell-based therapy would have two significant components: a way to kill cancer cells, and a way to specifically target them. In our quest to find a way to specifically target cancer cells, we found that the problem of controlling a cell’s interaction with its physical environment extended beyond cancer therapy into a myriad of biological contexts. Harvard iGEM 2015 focuses on building a platform for controlling specific bacterial adhesion in a variety of biological settings, including colon cancer therapy.
Looking Closely at the Problem
Explanation of how we thought through potential solutions in the context of the microbiome. Statistics and links to external sites about the prevalence of bacteria in the gut. Motivations from the perspective of synthetic biology to address the problem of colon cancer with the power of synthetic biology. However, we’re unable to use the power of synthetic biology.
Inspiration from Nature - Type 1 Pili
Enter Type 1 fimbriae. Start by saying that interaction with the physical environment is a huge problem in nature and has been worked on for billions of years. Make clear that we’re inspired by nature and that we’re mimicking nature’s design. In biological systems Type 1 Pili typically manifest as organelles on the surface of pathogenic E. coli which are responsible for urinary tract infections in humans. The pili are translated from the “Fim” system of genes in the E. coli genome. Formation of individual pili consists of a “chaperone-usher” pathway whereupon a fimD “chaperone” protein binds to a subunit of the pili and “ushers” it through a membrane pore to bind it to the elongating pilus. Repeating fimA subunits form the base of a helical rod roughly 7 nm in length, which are attached to two adapter proteins (FimF and FimG) and finally the FimH adhesin at the end of the pilus. The role which the pili play in these infections follows from its structure. FimH contains a mannose-binding domain which binds to mannose-containing receptors in host cells in the urinary tract epithelial tissue, activating a phagocytic process within the cells, leading to bacterial invasion and replication in the host cells (Wolf et al., 2002).
In the Fim genetic circuit, the FimE and FimB recombinases play an especially significant role in regulating expression of the Fim system and the resulting pili production. Containing an invertible 314-bp element called the “Fim switch,” the system is only able to be transcribed by the promoter when this switch is in the “on” orientation. FimE and FimB are located upstream of the rest of the Fim operon subunits.
Controlling Bacterial Adhesion
(Our Approach)
A Toolkit
Textual elaboration of the graphic. We won’t go into detail on the construct design here or the fusion sites on fimH; speak generally to the spirit and inspiration of our process, emphasize graphically the modularity and reusability of the system.
The problem of controlled bacterial adhesion spans biology and we mean to solve it! Our approach and the biobricks we have submitted to the registry will be a resource for future iGEM teams to control adhesion in a myriad of contexts.