Bioinformatics methods and application of biomarkers in precision medicine

1 Overview of precision medicine

In 2011, the term "Precision Medicine" appeared for the first time in the National Academy of Sciences meeting "Towards Precision Medicine: Building a Biomedical Research and Knowledge Network and a New Disease Classification System". Refers to the precise detection of various diseases and the specific targets of the main targets of early treatment through advanced biological protein and genomics and other modern technical means, and the precise subdivision of related diseases according to the different signs and symptoms of related diseases. To achieve the main purpose of targeted and precise treatment for specific populations and a particular disease, greatly improving the effectiveness of disease diagnosis, treatment and prevention.

With the completion of the sequencing of the Human Genome Project, at the same time, personal genomes and tumor medical genomes are moving towards a more extensive and diversified data-intensive research direction, a new medical basic theoretical technical concept and a new medical service model in the fields of medicine and biotechnology As the times require, "precision medicine" has emerged. One of the basic concepts of precision medicine is to achieve personalized precision medicine. With the rapid development of modern biogenomic medical sequencing analysis technology in China and the extensive crossover and comprehensive application of modern big data life sciences and bioinformatics, precision medicine has rapidly developed and grown. .

2Precision medicine based on biological information analysis method

2.1 Genetic screening of sensitive drugs

At present, there are three common methods for pharmacogenetic testing: fluorescence in situ hybridization, real-time fluorescence quantitative PCR, and gene sequencing1. Fluorescence in situ hybridization is the use of fluorescent probes to detect drugs or viral genes. Real-time fluorescent quantitative PCR can detect the expression of interfering mRNA in drugs, and use this as a basis to determine whether these related drugs have inhibitory effects. The technology of gene sequencing is to screen out potential genetic diseases and gene polymorphisms of therapeutic drug proteins by sequencing the entire genome of an individual before performing biological analysis of the genome. According to the differences in drug delivery and binding of target targets caused by individual differences in patients, more effective and precise treatment can be achieved.

2.2 Precise diagnosis methods for individual potential diseases and tumor screening

With the continuous development of sequencing technology, a large number of molecular markers for common and rare system diseases have been identified, such as Alzheimer's disease and Parkinson's disease1. Although there are many causes of diseases, the identification and determination of molecular markers is an effective method. They are considered to be one of the important methods for accurate diagnosis of diseases. Gene mutation detection technology is an important means to implement precision treatment. Clinical tumor patients often use tissue biopsy technology, but the test results are not completely accurate, and the false positive rate is as high as 65%. In contrast, genetic testing in bioinformatics technology can advance the early diagnosis of cancer to the cancerous stage of cells, providing genetic guidelines for the early prevention and treatment of tumors.

2.3 Application of omics detection technology in precision medicine

Omics technology detection is a core content of precision medicine, divided into a variety of research methods such as histology, transcription, genomics, proteomics, and metabolomics2. The main types of technologies related to omics genetic testing include molecular genomics testing, gene editing, and liquid biopsy technology. Gene editing technology is characterized by its ability to target specific genome sites. Gene editing technology is currently used in the treatment of stem cell diseases, such as gynecological malignancies. At present, the technologies that have been widely used in gene editing include CRISPR-related protein nuclease, zinc finger endonuclease, and traditional RNA interference.

2.4 The value of bioinformatics analysis in precision medicine

Bioinformatics is a discipline that uses computer technology to study the laws of biological systems. The research object of bioinformatics is a variety of biological data. Its research tool is computer. The research method includes the search for biological data (collecting And screening), processing (editing, sorting, management and display) and utilization (calculation, simulation). If bioinformatics is applied to the field of precision medicine, a biological sample database and information database can be established, and accurate assessment of diseases can be achieved through the analysis of massive data, so that breakthroughs will be made in both the fields of disease monitoring and prevention and clinical treatment.

Take the TCGA project in the United States as an example. Among the hundreds of studies published in the top scientific journals Cell and Nature^Science, about 70% of them are informatics analysis of tumor genomes. From this we can see that genomic informatics, an important branch of bioinformatics, occupies a very important position in tumor research. The application of bioinformatics technology in the field of precision medicine may detonate an era change in life science research.

3Precision medicine and biomarkers

The main focus of "precision medicine" is "precision". Precision medical research uses advanced genomics, proteomics and other cutting-edge bioinformatics analysis methods and science and technologya, and at the same time fully combines advanced cutting-edge medical technology H, to distinguish specific populations in some of the more important large samples The screening, demonstration and comprehensive application of various biomarkers have been carried out. By detecting the actual conditions of specific markers in different periods, personalized and accurate diagnosis can finally be realized. Biomarker (biomarker) is a kind of biomarker signal that is produced when the steady state of the organism's physiological environment undergoes certain natural changes, and subsequently changes.

3.1 Classification of biomarkers

3.1.1 Traditional biomarkers and research overview

Traditional biomarkers include proteins, polypeptides, fats, hormones, pathogen nucleic acids (usually used as active samples) and other molecules. The detection medium is mainly human hair, feces, tissue samples, etc. With the introduction of new technologies such as cell therapy and tumor immunotherapy, the main research goals and ideas of the biomarker system have undergone significant changes. Protein and its expression have become a new type of biomarker that is currently the world's mainstream.

3.1.2 Emerging circulating biomarkers and research overview

According to the latest research results, emerging circulating microbial markers can not only be widely used in the screening of germline mutations in the human body, but also widely used in somatic mutations. Screening. A very small amount of nucleic acid in tumor cells formed by somatic mutations can also be detected in the peripheral blood. According to the inspection objects of circulating biomarkers, they can be divided into three categories.

Circulating Nucleic Acid (CNA). Extracellular nucleic acid that exists in human plasma, serum, cerebrospinal fluid and other body fluids. It can perform early detection and diagnosis of patients, monitor the development of the disease in real time, follow up the development of the disease in time, and effectively evaluate the results of treatment.

Circulating tumor cells (CTC). A variety of tumor cells that exist in human peripheral blood. There is an obvious and close correlation between the results of the CTC count and the mortality of patients'6. It is also widely used in drug screening to achieve precise, low-cost and high-efficiency treatment7.

Exosome. Disc-shaped vesicles usually have a diameter of 40-100nm. A variety of cells can produce exosomes under normal or pathological conditions. Based on this, the tumor load level of early patients can be evaluated, and the effect and effect of immunotherapy can be accurately judged.

3.2 Application of biomarkers in the field of anti-tumor

One of the successful examples of the practical application of precision medicine in the treatment of malignant tumors'8 is that biomarker-based pharmacological anti-tumor targeted diagnosis and treatment are widely used in my country, making certain malignant tumor patients within 5 years Both the survival rate and disease remission rate can be improved to varying degrees9. The use of biomarkers to detect patient tumor samples, followed by the formulation of a reasonable treatment plan, has gradually become the mainstream anti-tumor treatment program'10. Although the efficacy of targeted anti-tumor drugs has improved significantly compared with previous years, there is still a long way to go to achieve true precision treatment, among which tissue difference is the biggest bottleneck.

The combined application of cytotoxic grade chemotherapeutics and other targeted therapy drugs can significantly improve the therapeutic effect. Especially for cytotoxic chemotherapeutics with relatively tissue-specific effects, learning from the treatment plan of targeted drugs can more deeply explore their mechanism and effects. The US FDA has applied a new clinical drug evaluation program '10, and the development of anti-tumor drugs has been accelerated. It is recommended that research institutions strengthen the research of signal pathways associated with the target in the early stage of anti-cancer drug development, and accurately screen the biomarkers of the people who benefit from the new drug, so as to accelerate the efficiency of anti-cancer drugs from the clinical trial stage to the approval of the market. Can save more patients' lives.

Precision medicine is regarded as the next generation of diagnosis and treatment technology, and has huge advantages compared with traditional diagnosis and treatment methods. Compared with general traditional medical treatment methods and methods, precision medical treatment has higher diagnostic accuracy and speed. On the one hand, gene sequencing only requires the patient to provide a certain amount of blood or saliva instead of using traditional biology. Pathological slices greatly reduce the impact on the patient's entire body during the diagnosis process. On the other hand, with the help of gene sequencing, genes related to cancer occurrence or mutation can be determined, and accurate medication can be used to greatly improve the diagnosis and treatment efficiency. The rapid development of precision treatment will significantly improve the diagnosis effect and cure rate of cancer patients, optimize the medical and health development model, rationally allocate medical resources, and build an efficient modern medical and health service system.

3.3 Pain points in the field of precision medicine

At present, an important pain point in the field of precision medicine is the lack of standardization of data analysis technology. As we all know, due to differences in biological sequencing equipment, experimental procedures, and analysis software, the sequencing results provided by different testing institutions vary greatly. At this time, the standardization of bioinformatics analysis is particularly important. The main purpose of the CGAC (China Cancer Gene Atlas Project) project is to establish a standardized process for tumor sample collection, transportation, storage, testing, bioinformatics analysis, and genetic consultation and interpretation, and form industry standards or expert consensus to avoid differences in report interpretation . This project can not only provide auxiliary diagnosis for industry experts in tumor precision medical diagnosis, but also provide a reliable and detailed scientific basis for the formulation of national standards based on NGS technology multi-gene panels.

4 Commonly used biopharmaceutical technologies

4.1 Cell Engineering

Cell engineering technology is a basic theory and key technology widely used in human cell molecular biology and human molecular cell biology. They can help produce useful or trace and small biological cell products or cultivate valuable protozoa or plants, and they can even help produce a new native species or new strain. Through this large-scale cell drug preparation production project, on the one hand, the production quantity and dosage forms of cell drugs can be greatly enriched, on the other hand, the production cycle of cell drugs can be greatly shortened, and a lot of waste of manpower and material resources can be reduced. Large-scale and process-oriented pharmaceutical factories are of great significance.

4.2 Genetic engineering technology

Genetic engineering is based on molecular genetics, with molecular biology and microbiology as the main methods. Different numbers and types of genes are used to construct a hybrid DNA molecule directly in vitro according to a pre-established blueprint, and then induce it to enter living cells. Change the original genetic characteristics in its biological system to obtain genetic science and technology for new varieties. Genetic engineering technology is mainly used in the preparation of insulin and interferon drugs. Genetic engineering technology has been applied to the study of gene structure and function, and has provided strong support for gene research. Hormones and active factors in the human body are usually indispensable for metabolism. Through genetic engineering technology, various hormones and active factors can be synthesized.

5 Development prospects of precision medicine industry

With the continuous progress and rapid development of the basic science and engineering technology of modern precision biomedicine in my country, the modernization of the precision medical industry has gradually developed and has become a component of a major strategic key emerging industry in our country. Judging from the analysis of the industrial structure development in the field of precision diagnosis medical technology and related markets in my country so far, due to the early development of the precision clinical diagnosis medical technology industry in China, the development of this technology has been relatively mature. In the whole of 2015, my country’s precision diagnosis The medical technology market occupies approximately 29.3% of the market share, far higher than its 17% in the entire world market.

The fundamental and key to the development of the precision medical and health industry lies in the rational use of new technologies such as genetic testing. At present, the relevant preferential policies of local governments in my country are gradually relaxing. Under the joint promotion of many important factors such as national policies, technology, market and economic development needs, and social funds, it is expected that my country's overall market size as a global precision medicine and equipment manufacturing industry will continue to maintain a good momentum of steady growth in the next few years According to the statistical data on corporate business strategic planning provided in the "Prediction and Investment Strategic Planning Analysis Report on the Development Prospects of the Global Precision Medical Equipment Industry", it is expected that the average annual growth rate of my country’s precision medical industry will remain at Around 20%.

Industry insiders conservatively analyze and estimate that by the end of 2024, the overall market sales scale of my country's precision medical industry may reach 135.6 billion yuan. As my country's precision medicine market, technology, and enterprise information management technology continue to mature and develop rapidly in recent years, it will be the future development trend of my country's precision medicine to promote the development of my country's medicine in the direction of precision medicine and personalized medicine.

Recently, many biotechnology companies in a relatively early stage of development have also launched financing activities. For example, the Hong Kong drug oncolysis, which has developed a biomacromolecule drug delivery carrier YB1, is carrying out Pre-A rounds of financing to accelerate their advancement. It is expected to enter the Hong Kong capital market as soon as possible in the future and usher in a new stage of development on a larger stage.

Hong Kong Medicine Oncolysis focuses on the two research directions of cancer immunotherapy and thrombolytic therapy for anti-thrombotic diseases. It is currently focusing on the development of oncolytic bacterial therapies and thrombolytic bacterial therapies through its core technology product biomacromolecule drug delivery carrier YB1 , And has laid out the corresponding innovative product pipeline.

Generally speaking, as an important bridge connecting the mainland and international capital, the Hong Kong market is relatively active in its own market and has a lasting appeal to global investors. It is indeed a good choice for mainland biotech companies to go public and raise funds. Reserve forces will continue to support the Hong Kong stock market in the future, and use "model forces" to create more surprises for the global capital market.