Systems Analysis of the Protein Secretory Pathway in Yeast and Human Cells
Doctoral thesis, 2015
The cell was discovered by Robert Hooke in 1665, later in nineteen century the cell theory was developed as all organisms are composed of one or more cells. Since then, many tools and experimental methods have been developed to dissect and characterize the cell components which resulted in established solid scientific fields such as biochemistry, molecular cell biology and genetics. These fields provided us with accumulated reductionist knowledge of components and processes in different cells originated from organisms belonging to various kingdoms of life, as simple as prokaryotes to the higher eukaryals. By the advent of biotechnology these knowledge is used to change many aspect of our life. One of the most important cell processes that has been core to this revolution is secretory pathway which is responsible to put proteins in the cell surface or extracellular space. These protein which are called secretory proteins, encompass diverse range of proteins in each cell with critical roles in digestion, cell-cell communication, signaling, physiology, connectivity etc. Recombinant gene expression was the fruit of the revolution in molecular biology techniques such as PCR in 1970s and using of host cells secretory capacity. A decade after, expressing a heterologous (foreign) proteins in host cells have revolutionized healthcare, agricultural, fuel, food and waste industries. These cells include a wide range from bacteria, fungi, to insect cells and mammalian cells. Nowadays, there are hundreds of biopharmaceutical proteins in the market with many more under clinical trials. Sequencing of complete genomes and the availability of genome-scale reagents has changed the experimental strategies for determining gene function. Besides genome sequencing other high-throughput methods have been developed to measure transcription, translation and metabolites and therefore we are now facing a lot of data on different cellular processes that are collectively referred to as omics data. Analyzing this kind of data is inevitable demanding the use of computers integrated with statistical and mathematical algorithms. However, this is only the starting point, as all these entities in reality work together in a complex networks of interaction resulting in important biological systems which is called emergent properties. Analyzing omics data without integrating them in the context of network give us very little and unrealistic view of the cell. Here systems biology, which studies biological processes as complex systems in the context of their interaction, comes to play. Based on reductionist knowledge we have been somewhat successful in using secretory machinery to produce many different proteins. Also we know a lot how the malfunction of this pathway can results in serious diseases. As we are now able to measure the activity of secretory pathway as a whole system and connecting it with the activity of rest of the cell, we may be able to use systems biology to elevate our understanding of the protein secretory pathway to the systemic level which is todays bottle neck in both protein production and human diseases related to this pathway.
flux balance analysis
secretory pathway: secretome