Computational biology reveals the immune system's ability to recognize invasive pathogens.
In the process of searching for the answer, Hannah Meyer, a researcher and bioinformatics expert at Cold Spring Harbor Laboratory in the United States, noticed a kind of white blood cells called T cells. This is a kind of lymphocyte, which plays an important role in immune response. After T cells are produced by bone marrow, they will reach thymus with blood flow, where they will "train" to mature. Thymus is the central lymphoid organ of human body, which is located near the heart and often divided into asymmetric left and right lobes.
Hannah Meyer pointed out that T cells can not only identify and destroy cells infected by foreign invaders such as COVID-19, but also send signals to other parts of the immune system to mobilize them when necessary. These functions depend on the ability of T cells to distinguish dangerous pathogens from human cells, which is acquired in the thymus. As for how to get them, we don't know yet. "We know that the thymus represents everything," Meyer said, "but we don't know how it is regulated."
Computer simulation
In the unique microenvironment of thymus, T cells and epithelial cells interact in almost infinite combinations and sequences. It is possible to observe these interactions directly in the laboratory, but if you try to explore them in an empirical way, it is like predicting the outcome of a chess game by trying every possible way. Hannah Meyer is designing a computer model that can simulate these combinations to determine which combinations are more important for the training of T cells in thymus. These results will make the research in the laboratory more targeted.
The laboratory research of immune cells and the computer model of immune response usually exist in their respective academic fields, and what Meyer is doing now is to integrate them into a more grand field, namely computational biology. She said: "We need to combine experiments and calculation methods to have a basic understanding of the true meaning of' health' and understand what may be wrong with some symptoms."
In Hannah Meyer's laboratory, the research team designed a program to simulate the environment experienced by T cells. They can add environmental variables, evaluate the possibility of various cell reactions, and conduct experiments to compare the model results with the actual behavior of immune cells. Their goal is to find out how Chu's newborn T cells are transformed into immune "warriors" against pathogens, and finally determine the relationship between infectious diseases, cancer, diet and immune system.
Color electron microscope images of t cells.
The journey of T cells begins in childhood, and immature T cells follow the trajectory of chemical signals and enter the thymus. T cells are produced in bone marrow, and initially only the necessary "receptors" are needed to detect these chemicals. Before leaving the thymus to fight diseases, T cells must develop an additional set of specific receptors, so that they can recognize all types of healthy cells, tissues and protein. Otherwise, they will eventually attack the wrong target. Hannah Meyer said: "T cells must know anything they may encounter in other parts of the body and will not migrate." Because the human body contains about 200 kinds and 30 trillion cells on average, each T cell needs very detailed "training".
This training comes from specialized epithelial cells in the thymus. These cells can present all protein fragments that T cells may encounter in the whole body, namely epitopes, so that T cells can learn to recognize the "appearance" of almost any healthy cells and tissues. Therefore, when T cells finally leave the thymus to perform the task of fighting diseases, they will know that any cell with unknown appearance must be foreign and can bring diseases and dangers.
Researchers have generally known that the training of T cells by thymic epithelial cells is mainly to make them "know" all protein epitopes of healthy people, but how to train them is still lacking in specific details. We don't know how this "training" is carried out, how many epithelial cells T cells need to visit to be considered complete, and whether T cells must contact different epitopes in a specific order. Knowing these details can explain the key difference between effective immune response and deficient immune response.
Two years ago, Hannah Meyer was studying another equally complicated question: What is the difference between a healthy heart and a heart prone to heart disease? Like the current research, she also turned to computer models and simulations to understand the key genes and physiological components that make the heart beat effectively. In order to bridge the gap between experimental research and model research of human heart, she developed a set of computer programs, including a "phenotype simulator", which can convert genotype (genetic information of organisms) into phenotype (observable characteristics of organisms). For example, brown hair is a phenotype, which is the result of genotype expression of hair color. This process of translation and output may be quite complicated, because phenotype will be influenced by a large number of environmental factors and internal feedback mechanisms.
Combination of simulation and experiment
Hannah Meyer is trying to apply computational methods to clarify the genetic composition of cardiac physiology in order to solve her most interesting biological problem: how thymocytes train T cells. In this study, her simulation allows researchers to insert several important factors (such as location and training duration) and then observe a series of immune-related characteristics that cells may acquire in response. The resulting data sets provide the "real situation" of different immune response modes in these simulated scenarios. By experimenting with different input variables, researchers can explore how specific cell interactions and relationships affect immune function. These results can also guide laboratory research and determine the related molecular changes in T cells.
? Hannah Meyer's colleague Samir Bai Ya is engaged in immunology research in Cold Spring Harbor Laboratory. He is particularly fascinated by using Meyer's calculation method to examine the relationship between cancer, diet and immune system. Studies have shown that a high-fat diet can lead to the formation of larger tumors in mice, which is obviously related to the weakening of the immune system's ability to clear cancer cells, but scientists do not know which fat-related processes lead to the weakening of T cells. Bai Ya said that there are too many variables and mechanisms at work, which is a kind of "multi-dimensional data confusion".
In order to solve this puzzle, Bai Ya cooperated with Meyer to find the causal relationship between diet and cancer phenotype through computer simulation. Without the help of computers, it may take us several years to realize this relationship. Computer analysis and simulation can bring new hypotheses, and then use these hypotheses to design experiments, so as to know whether dietary factors directly trigger the response or weaken the response through immune cells (such as T cells). Bai Ya said: "As a laboratory scientist, you never know whether something is regulating the process you are studying until you do a functional experiment, such as turning it off or over-activating it."
At the same time, Hannah Meyer also developed some new methods based on the previous successful software development to help Bai Ya and other experimental researchers identify these processes more effectively. She pointed out that the new program focuses on the interaction of individual cells, "treating each cell as an independent factor", allowing simulated immune cells to move naturally in the 3D grid and track their interactions.
Meyer wants to know whether different pathways and interactions in thymus and different interaction sequences have changed the immune function of T cells. These results will provide inspiration for subsequent experiments. For example, if her model shows that when T cells move along a certain route, they are more likely to fail and attack healthy cells, then researchers can design experiments to explore whether there is migration priority of T cells in thymus, or whether the maturation process of T cells depends on their location.
Genetics and immunology researchers all over the world began to use Meyer's program for research; Her genetic analysis software suite, including phenotype simulator, is provided free of charge and has been downloaded more than 34,000 times. The established user group can report problems at any time and help Meyer develop patches to fine-tune the specific research tasks of the simulator. "It is very important to make other people's work easier." Meyer said.
Of course, Meyer's plan is not to reveal a panacea that can strengthen the immune system on demand. "People want a formula to eliminate coronavirus pneumonia-19, but scientific research is not like this," Bai Ya said. "We don't even know the molecular and cellular basis of complex diseases. We need to understand these processes and how they interact. " Hannah Meyer's job is to provide such tools to help researchers finally understand these processes. Through continuous efforts, human beings are getting closer and closer to unveiling the mystery of the immune system.