Team:NAU-CHINA/IntegratedHP
HUMAN PRACTICES
Integrated HP
Developing Project
Based on Google Trends and our interests, we chose medical care, the hottest issue of recent society, as the field of our research, and cancer attracted our attention as the most concerned area in medical field. It is estimated that in 2014, the number of new cases of malignant tumors in China was 3.804 million (2.11 million males and 1.69 million females), and an average of seven people per minute was diagnosed with cancer (data from the National Cancer Center). According to the latest data released by the American Cancer Society in CA: A Cancer Journal for Clinicians, there will be 1,688,780 new cancer cases and 600,920 cancer deaths in the United States in 2017. Cancer is a global disease that threatens human health, and is the second leading cause of death in the United States. Statistics show that there were 1,688,780 new cases in the United States in 2017, which means that 4,600 new cancer patients were added every day[1].
CAR-T (Chimeric Antigen Receptor T-cell Immunotherapy) is a kind of immunotherapy that embedded an antigen receptor on T cell. An antigen receptor combines antibodies against specific tumor antigens with CD3ζ, FcεRIγ in T cells and expresses them on patient T cells in vitro. The engineered T cells are amplified, screened, and returned to the patient in large quantities. The basic principle is to use the patient's own immune cells to clear cancer cells, which is called a cell therapy rather than a drug one. CARs consist of intracellular signaling regions (for example, CD3ζ and CD28), transmembrane regions, and extracellular antigen-binding regions of the T cell receptor (TCR). Recombinant CARs rely on the antigen but not on the presentation of MHC, effectively avoiding the immune escape mechanism of MHC down-regulation
Cytokine storm refers to a variety of cytokines in body fluids such as TNF-α, IL-1, IL-6, IL-12, IFN-α, IFN-β, IFN-γ, and MCP. The rapid and massive occurrence of -1 and IL-8 is an important cause of acute respiratory distress syndrome and multiple organ failure. It is a side effect of CAR-T immunotherapy. In order to relieve cytokine storm, we developed a kind of engineered T cell, which can monitor and relieve cytokine storm automatically[2].
Improving Project
In order to solve the experimental problems coming out with the progress of our research projects, we came to Shanghai Institute of Biological Sciences (SIBS), Chinese Academy of Sciences (CAS) to conduct some interviews. This also plays an important role in education & public engagement.
We got ourselves well prepared for the interviews.
First, we browsed the website of the SIBS to determine the list of researchers to be interviewed. Considering the theme of the project, we selected several researchers who have made great achievements in the field of cancer treatment.
Prof. Wang Hongyan new mechanisms of inflammation regulated by immunocytes and inflammation-related diseases
Prof. Meng Feilong ways to suppress the occurrence of immune system tumors and important factors in various immunodeficiency diseases
Prof. Yang Chenghua malignancy molecular mechanism of tumorigenesis and development, and the development and mechanism of targeted therapy for small molecule drugs
Prof. Ji Hongbin molecular mechanism of lung cancer
Prof. Chen Jianfeng functional regulation of cell adhesion molecules in inflammation and cancer
In mid-July, 2018, we explained our interview intentions by email to these researchers, and appointed the interview time with them.
Secondly, we thoroughly reviewed the relevant works and scientific research results of these researchers, prepared the interviews in a targeted manner, and intended to ask them questions about their research directions. In doing so, we can not only understand the complete and authoritative information but also get closer to the respondents.
During the interview, we asked the respondents in detail about questions of cancer, cancer treatment, new therapies, immunotherapy, and the rationality of the pricing of cancer treatments in the current market. The researchers offered detailed answers. We have changed application field of our project from weakening cytokine storm to monitoring EFGR targeted cancer by following recommendations from the principal investigators in SIBS. The reason why we change the application field is that Synnotch cannot be used in the solution environment. Therefore, we change the target from different kinds of cytokines to EGFR, a kind of protein on the surface of the cell membrane, which can be bound with synthetic extracellular recognition domain of Synnotch effectively.
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, for example, non-small cell lung cancer and pancreatic cancer.
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.
More project application details are shown in application.
Application Research: Bigger Picture
As the work progresses, we recognize that our system can convert the external fluctuation signals into simple 0 and 1 signals to realize the function of the analog-to-digital converter. Our system is very suitable for information processing. If we can convert the expression signals into electrical signals through light sensing elements in the future, we can realize the image displayed on our LOGO ——converting biological information into electronic information, making the machine biological and making biology engineering.
We have broadened our thinking, and the application of the topic is far more than the therapeutic field.
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.
In the process of industrial production and environmental monitoring, by modifying the upstream channel, cells can identify their own products, metabolic wastes or miscellaneous bacteria, etc., and realize automatic adjustment of production according to external conditions or remind people to deal with corresponding situations.
We met with relevant practitioners in the above fields and showed them our project. We came to the Department of Oncology of the Third People's Hospital of Luoyang City, Henan Province, China, and conducted a simple interview with Dr. GuoJianfeng, director of the Oncology Department. Dr. Guo first was briefed on our iGEM project, and then he answered several questions about EGFR (record of this interview see attachments). We also interviewed several practitioners working in environmental protection fields. They also gave us a detailed explanation of the current problem-solving solutions in the related fields. In the future, we can replace T cells with any kind of cells, engineer them, and solve a series of social problems.
References
[1] Zhang Y H, University J M. Research Development and Situation of CAR-T Technology[J]. World Latest Medicine Information, 2018.
[2] Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL (July 2014). "Current concepts in the diagnosis and management of cytokine release syndrome". Blood. 124 (2): 188–95. doi:10.1182/blood-2014-05-552729. PMC 4093680. PMID 24876563.
Nanjing Agricultural University
College of Life Sciences of
Nanjing Agricultural University
Nanjing University
Chinese Academy of Sciences
