Release date: 2015-03-27 Lead: In early 2015, US President Barack Obama announced in his State of the Union speech a new large-scale research and development project “Precision Medical Planâ€, which aims to complete the genome sequencing of one million people and integrate these data in a few years. Open the way from genomic data to clinical applications. What is the basis and goal of the research project? How will it affect research, medical models, etc? The author of this article will give an answer one by one. For China, the future of “precise medical treatment†requires our own large-scale genomics data as the basis. The recent medical network hot word is "precise medical", because it is advertised by US President Barack Obama, and behind Obama, is the current director of NIH (National Institutes of Health) Francis Collins and NCI (United States of America) Harold E. Varmus, director of the Cancer Institute, has two big cows. These two characters manage the most important areas of research in American medical research. What is the goal of such a high-profile, large-scale research project? What impact will it have on scientific research? How will the future medical model be changed? Should China follow up? This article will answer the above questions one by one. 1 What is "precise medical care"? "Precision Medicine" (PM) is a medical model based on the patient's "customization". Under this model, medical decision-making, implementation, etc. are formulated for each individual patient's characteristics, and the diagnosis of the disease. And treatment is based on the rational selection of the patient's own genetic, molecular or cytological information. The tools used in precision medicine usually include molecular diagnostics, imaging, and corresponding software. The concept of precision medicine is an extension of “individualized medicineâ€, which is based on biomolecules and is more precise and individualized because of human diseases. It can be seen from the concept that the patient's individual genetic information (genome) is the basis of precision medicine, that is, detailed annotation of the genomic information, as well as clinical use, in order to ensure the implementation of precision medicine. The Precision Medicine Initiative is a new large-scale research and development project announced by Obama in his 2015 State of the Union address. The White House official website subsequently released details of the precision medical plan: In 2016, the US budget plan was allocated to NIH, the United States. A total of US$215 million from the Food and Drug Administration (FDA) and the National Office of Medical Information Technology Coordination (ONC) is used to fund scientific research and innovation in this area. It funded NIH 130 million for medical research on a million-person scale to promote awareness of health and disease; and laid the foundation for the formation of a data sharing mechanism; funded NCI's $70 million for tumor genomics research, and development is more effective Therapeutic methods of cancer. Undoubtedly, the investment included in the plan will accelerate the understanding of diseases at the genomic level, and provide the latest and best technologies, knowledge and treatment methods to clinicians, so that doctors can accurately understand the cause and select drugs for use. Avoid unnecessary waste and reduce the occurrence of corresponding side effects. 2 Read the human genome "天书" It is said that the human genome "Tianshu" completed by scientists from six countries and spent 10 years and spending $3 billion on the "Human Genome Project" (HGP) is the "password book" for deciphering human health and disease. ". However, since the HGP was announced in 2003, until the emergence of next-generation sequencing in 2007, although HGP has accelerated the pace of human genetic research to a large extent, it is difficult for ordinary people to actually feel what this picture brings to themselves. Variety. The core problem is that the "Tianshu" of the human genome is too long, and each person's "Tianshu" is different. Every word in this book may be "written wrong" and become a "false book", but not Read it again and pick up the wrong word. If you read it again, you will find it takes several years and it costs a lot of money. It seems that this book is unreadable by ordinary people. Since 2007, with the advent of high-throughput sequencing technology, a person's genome sequencing can be completed in a matter of weeks. The cover of Nature in November 2008, along with three personal genome maps including yellow, black, and Caucasian leukemia, opened the era of the "personal genome." Sequencing a person's genome has been reduced from billions of dollars to millions of yuan, but it is still expensive. Scientists have launched several large-scale genomic research programs, such as The Cancer Genome Atlas (TCGA), the 1000 Genomes Project, and the International Oncology Genome Project. (International Cancer Genome Consortium, ICGC), etc., trying to deepen the understanding of the genome by sequencing the genomes of tens of thousands of normal and tumor patients. With the beginning of 2014, Illumina announced that the Hiseq X10 system will reduce the price of a person's genome reagent to a thousand dollars, or 7,000 yuan, making the "human genome" possible. Subsequently, the UK first announced plans to sequence the 100,000 population, and the “Genome England†company was established by the “Department of Health†under the National Health Service. The UK's 100,000 genomics project aims to benefit patients through genomics through the creation of transparent ethics and scientific design projects. In this context, Obama "can no longer sit still", the United States, as the leader in sequencing technology, can not be left behind in genome application, so it is time to start the "precision medical plan." If it is too early, it will cost a lot. If it is later, it may delay the pace of genomic information for the benefit of mankind. The United States may also lag behind the UK in genome application. The Accurate Medical Plan will complete the genome sequencing of one million people in a few years and integrate these data to open the way from genomic data to clinical applications. The genome is the sum of human genes. To understand the information of the genome, the genome needs to be sequenced, called "whole genome" sequencing. When we have the data for genome-wide sequencing, just like the HGP map, we have already read our own "Book of Heaven". Of course, read-only is not enough. To comment on this book, where there are typos in this book, where the order is wrong, and where the page number is wrong, these errors may be the cause of the disease. At this time, we need a "standard Bible" to compare with it to know where it is different. The first "standard Bible" drawn by scientists is the one drawn by the "Human Genome" project. However, the "Tianshu" of the human genome has more than one. Scientists have spent several years drawing tens of thousands of "Tianshu" out. The more "Tianshu", the more accurate it is to find a replacement for each word. Read the book and see what it means to be different, so that we can really understand this "Book of Heaven." 3 How genomics data supports "precise medicine" Modern medical diagnostic models, generally symptomatic signs + auxiliary examination + imaging data, patients with the same or similar symptoms, will use the same treatment. For example, Warfarin, which is clinically used for anticoagulation, is widely used in the case of thrombotic diseases such as deep vein thrombosis. By interfering with the carboxylation of vitamin K-dependent coagulation factors II, VII, IX, and X, warfarin prevents these coagulation factors from being activated, and only stays in the precursor phase to achieve anticoagulant purposes. However, recent clinical observations have shown that although the same symptoms, but different individuals use warfarin individuals vary widely, and these differences are directly related to the patient's own genetic background, the US FDA revised in February 2010 Warfarin's drug specifications, because of the gene specificity of the dose, before the prescription drug, it is recommended to carry out genetic testing on CYP2C9, VKORC1, and drug dosage adjustment for different gene types. The example of warfarin tells us that different people have different genotypes and may have different pharmacokinetic and pharmacodynamic characteristics for the same drug, resulting in different drug effects. These are not available in traditional medical systems. In fact, "the drug is a three-point drug," the toxic side effects of the drug are also clinically faced problems. For the individual use of the gene, a good evaluation of the metabolism and toxicology of the drug can achieve an effective and safe effect of the drug. Targeted drug-related genetic testing like warfarin is already “after the factâ€. The real precision medicine is to master the genomic information first, and once the disease symptoms appear, it can be targeted to treat and even prevent the occurrence of diseases. For example, the drug-sensitive deafness (mtDNA 1555A>G) gene has been gradually promoted in China, and this genotype is a site on the mitochondria, which is inherited from the mother to the child in accordance with the maternal genetic rules. People with genotypes can cause irreversible drug-induced deafness if they use aminoglycoside drugs. Genetic testing to confirm the presence of drug-related deafness related genes, avoiding the use of the corresponding drugs, can effectively avoid the occurrence of drug-sensitive deafness. This kind of medication causes 5% to 12% of the 27.8 million hearing-impaired people in China, that is, 1.39 million to 3.33 million people can avoid convulsions through medication warning. I have been involved in the diagnosis and treatment of a cancer patient. This is a case of "glioblastoma". After the initial operation, conventional radiotherapy combined with temozolomide chemotherapy is effective. The initial treatment is effective, but relapse after 6 weeks. We also performed whole-genome sequencing of primary and recurrent tumors, analyzed tumor mutations, and found a target for the targeted drug bevacizumab (anti-VEGF monoclonal antibody). We used bevacizumab for treatment. Recurrent tumor treatment is effective. But after a few weeks, the tumor relapsed again. We again used the other mutation found in the genomic data for the drug sunitinib. This drug is generally used for the treatment of gastrointestinal tumors, not the standard treatment of glioblasts. The tumor drug, but this time we are convinced that the presence of the corresponding mutation in the tumor tissue, and the use of sunitinib on the basis of the consent of the patient and the family, the effect is very good, the tumor is quickly controlled. The reason why tumors are refractory is because the mutation itself is very complicated and the "heterogeneity" is very high. Therefore, the information based on qualitative and quantitative tumor genome sequencing and analysis is very valuable, which is more accurate and effective than traditional pathological reports. Treatment basis. The significance of whole-genome sequencing for personal medicine is that we can directly diagnose almost all known genetic diseases, understand the genes involved in drug metabolism and evaluate the effects of drugs, and can understand the characteristics of known traits and evaluate the risk of complex diseases. . In the first Chinese genome published, the researchers found that they have an allele of the severe deafness gene GJB2, suggesting that he may have deafness in the elderly, and can also infer the risk of congenital severe deafness genes in his offspring; his genome There is a tobacco addiction gene, and the tester himself is indeed a heavy smoker; at the same time, he predicts the risk of Alzheimer's disease. There is also an interesting story here. James Watson, the father of DNA, shared his personal genomic data with all humans in 2007. In an interview, Watson sparked a public protest because he claimed that African blacks were not as smart as Caucasians. However, after analyzing Watson's genome, the researchers found that 16% of his genes might have originated from an African-American black ancestor, while most European descendants only carried less than 1% of black genes. This suggests that there may be Africans among Watson’s great-grandparents or grandparents. This also reminds us that with our own genetic information, we can almost understand all relevant genetic information. Imagine that if everyone has their own genomic information and shares it, we can build a genetic map of a family around the world so that our genetic relatives can be found. 4 Research and medical models face changes The current disease research model is mainly based on the construction of animal models for experimental research. However, animal models of disease often differ from humans, and even successful experiments on animal models are often difficult to repeat on humans. The Precision Medical Program will also collect all possible phenotypic information and combine genes and phenotypes while sequencing the genome. After having large-scale genomic data, that is, the genomic data of millions of people, if we want to study a certain disease, even if the disease has a disease rate of only 0.1%, we can find 100 people at the same time. The disease, together with their genomic data, looks for commonality, looking for possible disease-causing genes through computer calculations and reasonable statistical algorithms and computational models. The research model of human disease will be changed from "hypothesis-driven" to "data-driven". The development of drugs will also be based on genetic information, to distinguish the different genetic basis of different patients, and then design and produce drugs. We can imagine that in the near future, based on large-scale genomic information, computers will be able to simulate the entire life process, predicting which diseases we may have, early detection, early diagnosis, and early treatment. "Precise medical treatment" or "individualized medical treatment" is based on the individual's genetic background, based on the individual characteristics of the patient to target treatment. Everyone in the future, including ourselves, has their own genomic information. In daily life, we can arrange a suitable lifestyle according to our individual characteristics to ensure a healthy and longevity. If you go to the hospital when you are ill, the doctor will collect the disease symptoms and signs, and refer to the characteristics of our genome to give appropriate diagnosis and treatment plan, and choose a treatment plan that is effective and does not produce obvious side effects. If it is a bacterial or viral infection, you can also find suitable antibiotics and antiviral drugs through genome sequencing. In the recovery period of the disease, you can choose the food that suits your body condition, which is conducive to the recovery of the body. Everyone can enjoy the real "precise medical treatment". In recent years, in addition to genomics, omics including proteomics and metabolomes are rapidly developing. These "omics" data are of great significance for us to assess our own health. Here is a reference example: Michael Snyder, the pioneer of "individualized omics" and director of the Center for Genetics and Individualization of Stanford University, who discovered his own abnormal glucose metabolism by regularly testing his own metabolism. By consulting a doctor, the doctor found that his glucose metabolism did not reach the disease level, but it also exceeded the normal value, but this change is not easy to find early in the clinic. This kind of symptom is called "pre-diabetes" in medicine. Generally, "pre-diabetes" to diabetes has to go through several years. If it is not adjusted in time, it will almost certainly develop into diabetes. The doctor suggested that Michael adjust his schedule and adjust his diet to join the exercise program. Michael adjusted his life according to the doctor's proposal and joined the exercise program. After two months of adjustment, Michael's pre-diabetes symptoms completely disappeared and returned to normal levels. 5 What are the risks associated with the use of genomic data? Genomic data, as an individual's "book of heaven," will be a major ethical and social issue if it is known to others. First, the genome is not just about itself, because our genes come from our parents and are passed on to our children. Therefore, our genetic information will not only affect ourselves, but also affect our loved ones. If there is a genetic defect, or if it has a certain risk, it is likely to be discriminated: the insurance company may also refuse to insure because of the existence of certain "defective" genes; the employer may be due to the presence of certain "defective" genes. Instead of hiring someone; the "elite" gene can also be an indicator of the distinction between "social classes" and may even be exploited by ethnic extremists. 6 Should China wait? The “Precision Medical Plan†is actually a continuation of a series of large-scale genomic research projects starting with the “Human Genome Projectâ€, but the author is more inclined to think that it is a new beginning, because the past genomics research has clinical application value. However, the scientific goal is more to set the decoding of the "genuine" of the human genome itself, not the application. The "precise medical plan" is aimed at directly accumulating and applying genomics technology and knowledge. It can be said that if the "Human Genome Project" is a basic research, then the "precise medical plan" is the "transformation" research. After this "transformation" process, the initial realization of the human genome project is finally realized, so that everyone can get their own genome. Benefit from the information. Some people may suggest that since the rich countries of the United Kingdom and the United States are sequencing the genome on a large scale, this large-scale sequencing work seems to be simple and repetitive, and it costs a lot; the data of genome sequencing cannot be patented; a large number of inputs cannot be fulfilled. "Economic benefits," then China can completely "sit and enjoy" and wait for them to publish data. Here, the author wants to explain that the genomic research in the United Kingdom and the United States will certainly benefit all human beings, but the genome of the yellow race differs from that of the white, and the same conclusion can be drawn from various large-scale genomic studies and clinical studies. People need their own large-scale genomics data to do the basics, in order to do the "precise medical treatment" of the yellow people themselves. 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