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Genomics, derived and developed from genetics in the 19th century, has experienced many paradigm changes, just like the development of the discipline of need. This is due to the development and integration of other disciplines and technological innovation, but the fundamental motivation has never changed, that is, to solve the problem of disease.
Genetic diseases require people to understand genes and genomes, from micro single base mutations to gene fragment changes, genome reconstruction, genome modification and gene expression regulation, can be inherited to offspring and become the molecular basis of genetic diseases.
In the last century, one of the changes in the paradigm of genetics is to expand the extension of the concept of genetic diseases, or to redefine genetics. Many diseases are found to belong to the object of genetic research. Almost all chronic non communicable diseases, such as cardiovascular diseases, metabolic diseases, neurodegenerative diseases, aging and tumors, are genetic diseases. They can occur at the level of germ cells, somatic cells, stem cells, and also at the apparent level. This challenges the traditional paradigm of genetic research. From a single perspective, a single level, a single technical method, it is difficult to fully understand the disease, and it is difficult to produce new solutions.
The theories and methods of genetics have promoted the emergence and development of genome sequencing. The development of genome sequencing has also integrated, replaced and developed the research methods of genetics. If the first generation of Sanger sequencing system is still in harmony with immunohistochemistry, traditional PCR (non quantitative PCR) and gene chip based on hybridization principle, then the next generation of sequencing (second generation sequencing or deep sequencing) has a great tendency to replace these technologies, especially the incomparable advantages of large segment gene fusion and pathogen diagnosis.
Genome sequencing brings in-depth understanding of the genome, but also brings a lot of data. While excited, it also brings trouble, that is, how big the systematic error is. It is because of the subjective bias of the sample preparation, library establishment, sequencing reaction and data analysis, and the systematic error of the technical system. In addition, how to interpret massive data, how much of the genome sequence information is associated with pathophysiological mechanisms, and establish causality. Although Mendelian randomized clinical studies developed in recent years have established causality between genes and diseases (PCSK9 and hyperlipidemia, cardiovascular events). However, to design and complete such a research requires a lot of resources and patience. There are also potential security and ethical issues in the storage and use of personal genomic information, which may deepen people's concerns and discussions about these data. How to define genomic medicine includes three aspects: disease needs, patient groups and disease solutions. How to position the business model of genome sequencing includes three important issues: technological innovation, market scale and product access.
The unmet disease demand is the foundation of all biomedical innovation and development, and the value foundation of all biomedical industry research and development and business. Genetic diseases are the areas that benefit from genomic medicine first. There are more than 7000 single gene genetic diseases. It is estimated that there are 16.8 million patients with rare diseases in China. In May 2010, medical genetics branch of Chinese Medical Association held a "expert seminar on the definition of rare diseases in China" in Shanghai. It was suggested that diseases with an incidence rate of less than 1/500000 or less than 1/10000 of newborns could be defined as rare diseases in China. The total number of patients with rare diseases in China was estimated to be 16 million 800 thousand. These patients have no choice but to bear the pain of these genetic diseases, but there are still few treatments. Thalassemia is the most common autosomal genetic disease, and the incidence rate in China is about 8% (no recent epidemiological data). Currently, transfusion therapy and iron removal drugs are only symptomatic treatments, and cannot remove the cause of disease. Gene editing technology can increase the expression of globin by reducing the expression of BCL11A gene in autologous hematopoietic stem cells through in vitro editing, so as to provide solutions from the etiology level, which undoubtedly brings inspiration and hope for the solution of many genetic diseases. At present, there are still few pharmaceutical companies focusing on genomic medicine solutions for genetic diseases. In addition to the objective factors of technical strength and capital, the R & D cost and risk are very high. There are few people after the drug is put on the market, and the treatment cost is very high, which is far beyond the affordability of patients. It is a very important obstacle that it cannot bring considerable benefits for enterprise.
Oncology is the most powerful field of genomic medicine. With the development of genome sequencing and markers, there are great progress in molecular typing, treatment and targeted therapy, as for lung cancer and breast cancer with high incidence rate. Some second-generation sequencing for fusion gene detection also determines whether patients benefit from the treatment drug (drugs for NTRK fusion gene mutation). With the development of immune-oncology and the success of therapeutic drug research and development, CTLA4 and PD1 / PD-L1, which are targeted at immune checkpoint, not only prolong the overall survival of patients with melanoma, lung cancer and other tumors, but also deepen the attention and exploration of tumor cell biology and tumor tissue microenvironment. We are now beginning to realize that tumor cell biology is not invariable, but has the characteristics of evolution. Tumor tissue is highly heterogeneous, and it is an ecosystem in which a variety of cells and microenvironment interact. In this complex system, it is difficult to solve the fundamental problem with a single treatment scheme and drug, and the result is that tumor recurrence and metastasis are inevitable. Single cell sequencing provides a new solution for studying this heterogeneity and complexity. Single cell genomics, which consists of single cell transcriptome, single cell genome, single cell epigenome, single cell proteome and metabolome, will develop into single gene genomics medicine.
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