A wide range of bacterial species are known to localize to tumors after intravenous (IV) injection. This occurs for a wide variety of solid tumors, including brain, and breast cancers. These microbes impart their selectivity for tumors by exploiting the hypoxic microenvironment (i.e., low oxygen concentration), poor immune surveillance, and the increased availability of nutrients. This provides an additional cue that could be exploited to restrict infection to the tumor microenvironment (Figure 1). Using a genetic engineering approach, the capacity of bacteria to invade mammalian cells can be linked with the density of bacteria by placing invasin under the control of a simple hypoxia sensing genetic circuit.

Figure 1: Design for induction- dependent invasion of a cancer cell. Under conditions of low cell-density or normal aerobic growth, engineered bacteria are non-invasive. Above a critical cell density or in a hypoxic environment, sensors are activated resulting in the synthesis of invasin from the bacteria and the invasion of tumor cells.

1. a) In a table, demonstrate all the possible input and output of this hypoxia sensing genetic circuit. Assume that low cell density and aerobic condition is considered the same condition, and the high cell density and hypoxia is another condition; in other words, do not consider cell density and oxygen concentration as two different types of inputs (Hint: First of all, define what are 1 and 0 for your different inputs and outputs). (1%)
2. b) If you are to further improve the specificity of the current genetic circuit to target cancer but not other normal cell types, you are going to add an additional input to the circuit which is necessary to trigger the release of invasin. What type of logic gate will be involved? (0.5%)
3. c) Draw the logic gate chosen in 1b) and label the input and output terminals. (2%)
4. d) Assume that the new input is a cytokine level [Ctumor] secreted specifically by tumor cells, and that the invasin will only be secreted when the bacteria sense both hypoxia and high [Ctumor]. In a table, demonstrate all the possible input and output of this modified 2-input genetic circuit. (Hint: First of all, define what are 1 and 0 for your different inputs and outputs). (2.5%) 

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