B i n d . D e t e c t . S e c r e t e .
Team:IISER Tirupati/Description
The aim of Coca Coli is to design a bacterium that helps combat colon cancer in a cost-effective and targeted manner. But, what makes our bacterium special?
Armed with a Recognition Module and a Secretion Module, the Coca Coli navigates the gut until it spots its target: The Tumor.
It then binds to the tumor without any off-target binding and uses a potent weapon: Interleukin-12.
IL12, our secret weapon, then recruits its other brethren from the immune system and cause tumor suppression, finishing the act in style.
Now let's get scientific.
1. Specific Binding
In order to minimise off target effects, Coca Coli has modified fimbriae having a colon cancer homing peptide: RPMrel. This peptide has a unique feature of specific binding to Colon Cancer cells. Through this, we achieve our first layer of specificity.
2. Lactate Sensing
As a second layer of specificity, Coca Coli uses a hallmark of cancer cell microenvironment: high lactate production. Our probiotic therefore is able to sense the lactate levels and be triggered only when lactate levels cross the threshold characteristic for colon cancer cells. Specificity: double check.
Tumor Recognition and Response Module
A major obstacle in dealing with cancer is the lack of efficient targeting. Chemotherapy has undesirable side-effects due to off-target effects. Newer targeted therapies harnessing antibodies are effective but costly. Our probiotic is designed such that it can target colon cancer cells specifically. This consists of a double-proofing system, to ensure that IL-12 is released only in the tumour microenvironment.
- The DH5a strain of Escherichia coli contains appendages called fimbriae on their surface, which assist in cell-cell adhesion. Using this as a base, we will express a colon-tumour homing peptide, RPMrel on the fimbriae. Hence, the cell-cell adhesion of the bacterium is made specific to colon cancer cells.
- Warburg effect in cancer cells results in a higher lactic acid concentration in the tumour microenvironment compared to normal cells. We use this difference in lactic acid concentration as a switch to control the expression of Interleukin-12 which will be involved in tumour suppression. The IL-12 promoter is optimised, such that transcription occurs only at a specific range of lactate concentrations.
Tumor Clearance Module
The "drug" we chose is Interleukin-12. IL-12 is an anti-inflammatory cytokine, involved in the regulation of cell-mediated immune responses. Recent studies have shown that through a complex signalling cascade, IL-12 reduces tumour growth, and this makes the cytokine a hot topic of current research. Synthesis of IL-12 is under the control of the lactic acid promoter, lldPRDp optimised by the Recognition Module. Along with the structural sequence of IL-12, we conjugate a carrier protein, YebF for the extracellular secretion of IL-12, inspired by Solution.
"We play with bacteria and sometimes they play us"
Contact us
Email: igemiisertirupati@gmail.com
Address:
Indian Institute of Science Education and Research, Tirupati
C/o Sree Rama Engineering College (Transit Campus),
Rami Reddy Nagar, Karakambadi Road,
Mangalam (P.O.) Tirupati -517507.
Andhra Pradesh, INDIA
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