Shanghai Xinfan Bio: "Precise Medicine" must be interpreted with caution - Huaqiang Electronic Network

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In early 2015, US President Barack Obama said in his State of the Union address in the US Congress: "I hope that a country that has eliminated smallpox and mapped out the human genome map can lead a new era - an era of correct treatment at the right time. Later, I will launch a 'precise medicine' initiative that will take us closer to curing diseases such as cancer and diabetes so that everyone can get the personalized information they need to keep us and our families healthy."

This speech made "Precision Medicine" (sometimes translated as "precise medicine") quickly become a hot spot in the world at the beginning of the new year. According to the Chinese Physician Association newspaper "Physician" reported on March 26: Professor Wang Yongjun, vice president of Beijing Tiantan Hospital, recently revealed that the Ministry of Science and Technology has held the first national expert meeting on precision medicine strategy, and China's precision medical plan will be in the second half of 2015 or next year. start up.

Obviously, we need to think about why we should start an accurate medical plan at this time? How can I achieve the goal of precision medicine?

Why start precision medicine Faced with the physiology and pathology complexity that is urgently needed in the current biomedical field, some people have seen the challenge and some have seen the opportunity. "Accurate medicine" came into being at such an important turning point in life sciences and medical practice.

In the early 1990s, the US-led Human Genome Project was launched with the goal of determining the order of 3 billion nucleotides on the DNA of the genetic information vector owned by humans. In February 2001, the Human Genome Sketch was released; on April 15, 2003, F. Collins, the head of the International Human Genome Project and the current National Institutes of Health (NIH), announced that the human genome sequence map was successfully mapped. On the same day, the heads of government of the six countries including the United States, Britain, Japan, France, Germany and China jointly issued a statement congratulating the completion of the Human Genome Project.

The Human Genome Project is highly valued by governments and scientists because it is hoped that this program will decipher all the genetic information of human beings, thus providing significant assistance in safeguarding human health and fighting disease. After the announcement of the Human Genome Project in 2003, the researchers immediately launched the International Human Genome HapMap Project, which is dedicated to population-level genetic variation studies, to reveal genomic variation profiles for African, Asian, and European populations.

People have high hopes for the clinical application of genome sequencing technology. For example, in the field of oncology research, NIH launched the $100 million "The Cancer Genome Atlas" (TCGA) research project in 2006, and plans to map 10,000 tumor genomes. In 2008, the International Cancer Genome Consortium (ICGC) was established, followed by 16 countries participating in the research program on tumor genomic variation maps; at that time, the organization's goal was to target 50 different types of tumors, each The tumor was collected from 500 samples for genome sequencing studies. The TCGA project was completed at the end of 2014, and the researchers found nearly 10 million tumor-related genetic variants. Through statistical analysis of 21 cancer mutation data obtained from the TCGA project, the researchers showed that some clinically useful mutation sites can be found using genome sequencing methods.

However, while genome sequencing efforts are rapidly advancing, researchers are gradually recognizing the limitations of genomic knowledge. In the 10th year of the Human Genome Sketch, people published a series of articles to review and reflect. For example, the United States "Science" magazine published a review article entitled "Waiting for the Revolution", the main point is: "The determination of human genome-wide sequences has not brought about significant advances in basic medical care; thus prompted people to think, What is the reason for delaying the genome revolution in the field of health medicine?" Why are people's expectations and realities so far apart? In Nature's 10th Anniversary of the Human Genome Project, a review article entitled "Life is Complex" gives the answer: "The more biologists see, the more complex they appear." Although the DNA sequence of a genome is the genetic basis of an organism, life activities cannot be achieved simply by relying on base sequences.

We know that modern life sciences are built on the “central rule” that explains the transmission of genetic information. It has long been believed that the "central rule" ensures the "high fidelity" of the genetic information of an organism: the mRNA sequence must be strictly determined by the DNA sequence, and the amino acid sequence of the protein must also be strictly determined by the genetic code on the mRNA sequence. However, scientists in recent years have shown that the process of transmitting genetic information to RNA and proteins is full of various variations or "errors." In other words, the complexity of life is far from being clarified by simply determining the genomic nucleic acid sequence. Even at the level of DNA, RNA, and protein molecules directly involved in the “central rule,” genomic nucleic acid sequences are just the “tip of the iceberg” of life complexity; not to mention, life complexity involves epigenetic phenomena, and The involvement of small molecules of metabolism and glycolipids; not only that, but life complexity also involves different levels of cells, tissues and organs.

In March 2014, Cell Magazine released an album to mark the 40th anniversary of its founding, and its theme was called Complexity. In the album, R. Weinberg, a famous American oncologist, published a review article entitled "Complete Cycles - From Endless Complexity to Simplicity to Complexity", which emphasizes: In the past For 40 years, scientists engaged in oncology research have faced the confusion of countless incomprehensible pathological phenomena, the belief that reductionism must win, and the renewed complexity of the disease in recent years.

In the face of the current physiology and pathological complexity that needs to be solved in the biomedical field, some people have seen the challenge and some have seen the opportunity. "Accurate medicine" came into being at such an important turning point in life sciences and medical practice. The US Academy of Sciences Research Council published in a more than 100-page research report published in 2011: "Towards Precision Medicine - Building Knowledge Networks for Biomedical Research and New Disease Classifications" (hereinafter referred to as "Towards" Precision medicine"). Thus for the first time, the concept of “precise medicine” was clearly put forward, and the core tasks required to achieve this goal were systematically discussed. According to the author of the report, the premise of achieving "precise medicine" is to build a biomedical research knowledge network based on biological big data, and a new disease classification method based on molecular biology; by establishing an integrated type Biological data and knowledge, an individual-centric information sharing platform, can form a biomedical knowledge network to understand and acquire highly complex influencing factors or pathogenesis that are decisive for personal health; Knowledge networks will help to establish new disease classification systems that define new diseases or molecular typing and drug stratification for disease diagnosis and accurate treatment. The authors of the report emphasize that “the main benefit of the proposed disease knowledge network and the new taxonomy is 'exact medicine'”.

How to achieve an accurate individual-centered biological database that integrates different data layers and a highly connected knowledge network are necessary conditions for precision medicine.

The author of "Towards Precision Medicine" believes that "the establishment of a knowledge network and its research and clinical application depend on whether it has a large, multi-level, fully integrated database of human disease knowledge." In such a database, knowledge about human diseases includes not only phenotypic information such as clinical diagnosis and pathological analysis, but also various biomolecular information, including genomes, transcriptomes, proteomes, metabolomes, lipid groups, and superficials. Genetic group, etc.

In other words, the basis for conducting precise medicine is the need to have as complete individual biological data as possible. In early 2015, NIH Director F. Collins and H. Varmus, Director of the National Cancer Institute, expressed the same view when describing the proposed US Accurate Medical Program: “We are preparing to build a multi-time span of more than 1 million people. The US population 'cohort', they volunteered to participate in the study. Participants were asked to agree to a comprehensive biological analysis (including cell types, proteins, metabolic molecules, RNA and DNA, and genome-wide sequencing when funding permits) And behavioral analysis, all of these analytical data will be linked to their electronic health records."

This kind of database is not a routine bioinformatics database that simply collects certain types of biological data, such as "GeneBank." If a class of biomolecules or a phenotype is treated as a variable and the data of the same variable forms an information layer, then the database is a multi-level structure consisting of many variables, each layer containing a disease-related variable information. . It should be emphasized that with bioinformatics and computational biology techniques, one can discover the interrelationships between various molecules and establish a high degree of internal linkage between various types of biological data layers to form a complex Biomedical knowledge network. For example, mutations in the genome are associated with epigenetic changes, or with changes in proteome expression, and so on. Ideally, each information layer is intimately connected to other information layers. The high degree of integration between these different types of biomolecules, biomolecules and phenotype/clinical symptoms will help people discover pathogenic factors or diagnostic markers that traditional methods cannot exploit, and benefit people to specific individual patients. Perform accurate personalized diagnosis and treatment.

Obviously, such a biomedical knowledge network reflects the core feature of systems biology - multivariate integration. Systems Biology is a new interdisciplinary subject in the field of life sciences in the 21st century. L. Hood, an American scientist who is one of the founders of systems biology, believes that system biology is characterized by studying the composition of all components of genes, mRNAs, proteins, etc. in a biological system, and the interrelationships between these components under specific conditions. . Therefore, the core of systems biology is integration, first of all, to integrate different kinds of molecular components in biological systems for research; secondly, for multicellular organisms, system biology must also be from genes to cells, to Organization, integration to all levels of the individual. That is to say, the biomedical knowledge network that needs to be constructed "towards precision medicine" is based on system biology.

In order to advance system biology in the medical field, the European Commission has established a Coordinating Action Systems Medicine Consortium (CASyM), which involves research organizations, foundations and companies in nine European countries. In June 2014, the European Commission issued the “CASyM Roadmap”, which includes recent (2.5 years) and long-term (10 years) research programs for Systems Medicine. The roadmap states: "Systematic medicine is the application of systems biology approach to medical concepts, research and practice," and believes that "systematic medicine will revolve around the concept of 'patient-centered' in the next decade. To conduct medical research and practice, these activities need to integrate different disciplines, including mathematics, computer science, data analysis, biology, and clinical medicine, ethics, and social practice. Obviously, this road map and the report "Towards Precision Medicine" are said to be "different."

The “patient-centered” concept is also the key to the “Make to Precision Medicine” authors to build a disease knowledge database and knowledge network – “It is important to emphasize that the novelty and ability of this information sharing platform lies in 'Individually centered'. The database needed for precision medicine is to establish a high degree of internal linkage between the various types of biological data obtained from individual individuals.

How to build an individual-centric data repository? An article published in the journal Cell in 2012 can be used as a template. A US scientist performed phenotypic monitoring and blood sample analysis for 14 consecutive months, and obtained a complete individual such as phenotype, genomic sequence, transcriptome expression profile, proteomic expression profile and metabolite expression profile. The “multi-omics” data, and the integration of these different kinds of data through bioinformatics tools, established a database called “integrative personal omics profile” (iPOP). As a similar work, in March 2014, L. Hood and his American Institute of Systems Biology launched a research project called “The Hundred Person Wellness Project”, which plans to select 100 in 9 months. Healthy individuals conduct individualized multi-omics studies from molecular to phenotypic. L. Hood believes: "The basis for this individualized component is that each individual is unique in both genetics and the environment, and they need to use their own as a control at different time periods to analyze the individual from health to suffering from some kind of The transformation of the disease." The Institute plans to launch a research program called “100K” in the next five to 10 years to conduct this multi-omics research for 100,000 healthy people. The “Accurate Medicine Program” that NIH plans to launch in 2015 is also an individual-centered multi-omics data integration study that extends the number of studies to 1 million.

That is to say, an individual-centered biological database that integrates different data layers and a highly associated knowledge network are necessary conditions for precision medicine. “'Accurate medicine' is designed to provide each individual with the best medical care available. This information cannot be achieved without a significant reorientation of the information systems that researchers and healthcare providers rely on. The system must be individualized just like the type of medicine they are prepared to support. Universality must be based on a large amount of individual information; and the opposite of such a process will fail. Obviously, if the analysis process is just Initially, the biomolecular expression profile, individual-specific data and health history are stripped from the individual, and the information necessary to determine health and disease determinants is lost. So wrote in the report "Towards Precision Medicine."

From the above discussion, we can see that "accurate medicine" is a complex concept with rich connotations, which requires people to seriously think and carefully interpret. For example, “precise medicine” cannot simply be equated with “personalized medicine” because traditional Chinese medicine is individualized medicine, but not precise medicine; for example, genome sequencing is one of the main tasks to achieve “precise medicine”. But the realization of "precise medicine" cannot be limited to genome sequencing. On the other hand, we must realize that the emergence of “precise medicine” will have a major impact on biomedical research and medical practice, and may change the traditional model of human health and disease resistance.

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