From Mosfet to MOSFET

Our system can convert the external fluctuation signals into simple 0 and 1 signals to realize the function of analog-to-digital converter. At the same time, as a result of the introduction of recombinases, our system will theoretically be more accurate as a biological switch, with lower leakage, less signal expression affected by the concentration signal of external inducers.

Due to the characteristics of recombinases, the engineered cells of our subject can change the signals of different concentrations from the outside into two kinds of simple outputs, and the threshold can be changed by changing type of the promoter and the recombinase.

Based on these considerations above, our engineering cells can be used in the following situations

Precise targeted therapy for solid tumors

EGFR (epidermal growth factor receptor) is a protein that exists on the surface of both normal cells and cancer cells. EGFR is very important for cell growth and differentiation. When a cell's ligand binds to EGFR, EGFR will be activated, which will send a signal to the inside of the cell to control cell growth through the cell pathway.

However, compared with normal cells, many cancer cells have mutations that overexpress EGFR. When the ligand is attached to the mutated EGFR, this signal will remain " sent" all the time, resulting in uncontrolled cell growth and response. Different EGFR mutations lead to different kinds of cancers, such as non-small cell lung cancer, pancreatic cancer, breast cancer, medullary thyroid cancer, head and neck squamous cell cancer, colorectal cancer, chordoma, and malignant glioma.

Because the traditional cancer treatment methods, such as radiotherapy and chemotherapy, can kill all the rapidly growing cells while killing the cancer cells, there will be great side effects. Targeted therapy may also have certain side effects because the target also exists in normal cells. Immunotherapy may also damage normal cells due to the strong immune response of the modified T cells, so it is necessary to use an immune checkpoint inhibitor to adjust the intensity of the immune response. However, the use of immunosuppressive agents can also do some harm to the human body.

If we replace the upstream extracellular domain of our subject with EGFR antibodies, our design can accurately identify EGFR with different densities on the cell membrane surface, and judge whether the cells change according to the density of EGFR, thus realizing the recognition of cancer cells. Moreover, we can adjust the immune strength of the engineered immune cells and the threshold value of EGFR recognition by adjusting the promoter strength and the type of recombinase, so as to accurately distinguish normal cells with low density EGFR from cancerous cells with high density EGFR, protect normal cells to the maximum extent, and recognize and kill cancerous cells. We come up with two strategies to achieve this.

1. Make the whole set of switch final secretion PD - 1 antibodies and PD - L1 antibodies, such as MPDL3280A, MEDI4736 BMS - 936559, Nivolumab and Pembrolizumab, so as to make the T cells through other surface molecules to identify and kill cancer cells. Compared with the direct use of antibodies for injection therapy, our method of modifying T cells makes the antibody therapy more targeted and minimizes the damage to other immune cells in the body.

2. Make the whole set of switch finally secrete some molecules such as IL-12, CCL21 and so on. These molecules have the function of collecting T cells, thus strengthening the ability of T cells to kill cancer cells.

More future application prospects

In addition, by replacing the identification object of the upstream system, the measurement of a certain substance can be realized. By adjusting the types of downstream promoters and recombinases, the system threshold can be adjusted.Then the system can not only detect the presence or absence of substances but also dynamically detect the concentration of the detected substances .

If we install our system in two kinds of cells so that they can recognize each other and inhibit each other, then we can realize the function of group sensing, which can keep the number of two kinds of cells fluctuating within a certain range. And this will play a important role in industrial production, material detection and other fields. If the cells are made to emit fluorescence, the periodic brightness changes of fluorescence can be seen through periodic fluctuations in the number of cells, thus realizing the function of repressilator.