Molecular diagnosis mainly refers to the detection of structural proteins, enzymes, antigenic antibodies and various immunoactive molecules related to the disease, as well as the genes encoding these molecules.

From the technical level, molecular diagnosis can be understood as molecular biological diagnosis.

For both protein detection and gene detection, the technologies used include enzyme digestion, electrophoresis, molecular hybridization, PCR amplification and DNA sequencing.

 

History of molecular diagnostics

 

In the 1950s, Watson and Crick proposed the DNA double helix structure model, which marked the birth of molecular biology as an independent discipline and the breakthrough of a lot of basic work.

The liquid phase molecular hybridization established by Hall in 1961 opened the door to molecular diagnosis of diseases.

In 1966, Crick and Ochoa et al. decoded 64 human genetic codes and established the central law of biological inheritance: the flow direction of genetic information is dna-rna-protein, which explains the causes of diseases from the molecular perspective.

Since the 1970s, molecular biology has become the most dynamic frontier of life sciences.

 

Molecular medicine (individualized medicine) was born because of the theory and technical methods of molecular biology were applied to clinical practice continuously and played a very important role in the prevention, prediction, diagnosis and prognosis of diseases (4P medicine).

In 1975, Sanger and Gilbert established nucleotide sequence analysis in DNA molecules.

In the late 1970s, Kan et al. [1], a chinese-american scientist in the national academy of sciences, successfully performed the genetic diagnosis of sickle cell anemia by using liquid phase DNA molecular hybridization, marking the beginning of the era of genetic diagnosis.

 

After the discovery of reverse transcriptase, the concept of polymerase chain reaction (PCR) proposed by Mullis in 1983 led to a second revolution in molecular biology, which made it possible to obtain target molecules while also making molecular diagnostic techniques easy and easy to manipulate.

Biochip technology was also proposed in the 1980s. According to the fixed probe on the chip, Biochip includes: gene chip, protein chip, tissue chip, etc.

It has strong sample processing capacity, wide application, high automation and high throughput, and has a broad application prospect.

Among them, gene diagnosis is detected from the level of disease genes or disease-related genes and their expression products, which is more advanced and close to the nature of the disease, and realizes the early diagnosis of the disease.

 

Genetic diagnosis method is based on modern molecular biology technology and organically integrates cytology, genetics, immunology and other technologies, making genetic diagnosis more accurate, automatic and fast, thus greatly improving the specificity and sensitivity of diagnosis.

In 1991, the first somatic gene therapy program for genetic diseases was approved in the United States. Adenosine deaminase (ADA) gene was successfully introduced into a 4-year-old girl with severe complex immunodeficiency syndrome (SCID).

In the same year, fudan university successfully conducted the world's first clinical trial of gene therapy for hemophilia B.

In 2003, with the completion of the human genome project, translational medicine was born, and the application of molecular diagnosis continued to expand.

At present, the development of gene detection technology is the most rapid, mainly PCR, sequencing, gene chip technology as the core.

At the same time, molecular diagnostics are making further progress towards the detection of transcription and translation.

 

At present, molecular diagnosis is mainly used in the diagnosis of infectious diseases, genetic diseases, tumor and personalized medicine (treatment), health and epidemic prevention, disease risk prediction, efficacy monitoring, military (biological and chemical weapon countermeasures) and other aspects.

The problems of molecular diagnosis mainly lie in accuracy, stability and complexity.

In addition, the traditional regulatory systems and laws and regulations in China and the United States are relatively sophisticated in the development of the molecular diagnostic industry, and the traditional medical thinking model of doctors has not changed much.

However, due to the strong advantages of molecular diagnosis potential and technology, through continuous development and update, the role of more and more, greatly promote the development of modern clinical diagnostic medicine.

China and the us are trying to find a regulatory balance as soon as possible, while making some concessions in their regulatory systems.

 

Chinese and American scholars respectively described the molecular diagnosis industry and provided some development ideas.

At present, there are more researches on the American molecular diagnostic industry and less researches on the domestic industry, but they are all in the initial stage.

 

Overview of molecular diagnostic research in the United States

 

The United States leads the world in molecular diagnostic technology, occupies the first place in the market, and is the first to carry out diagnostic projects.

The journal of molecular diagnostics, published by the American society for research pathology and the society for molecular pathology, marks the development of genetic diagnostics as a mature discipline -- molecular diagnostics.

A 2001 article in the journal of molecular diagnostics, "here comes the FDA," noted that the U.S. food and drug administration (FDA) would intervene in the use of genetic techniques to diagnose diseases.

The FDA will focus on the inspection and evaluation of family genetic and molecular diagnostic methods and laboratory qualifications;

The principle, procedure, scope of application, reporting method, and consistency with clinical diagnosis of the experimental method were demonstrated, and a comprehensive quality control system of genetic testing was established in the United States to define the reporting mode and the range of information feedback to the subjects.

The purpose of this program is to perform molecular diagnostics safely, efficiently and legally.

 

According to Gene tests, a website run by the national center for biotechnology information (NCBI), 3007 genetic diseases had been identified by May 2013, of which 2,776 had entered clinical testing and 231 were still under study.

In 2011, Young published molecular diagnostics: the potential ripple effects of modified coding, which focused on the challenges to the management of molecular diagnostics companies and proposed solutions.

In 2012, Kevin published a research organization's efforts to control genetic diseases, which analyzed how much a research institution engaged in molecular diagnosis could contribute to society.

He thinks the agency could reduce its financial losses by $20-25m in 2010 alone.

The engineer reports on several cases in which venture capital helps companies enter the market for molecular diagnostics.

 

According to 2012: trends in diagnostics, molecular diagnostics is a hot topic for future development.

Doug published "the real need for rapid molecular detection in hospitals under the operating systems of apple and Microsoft", which explored the rapid development of the molecular diagnostic industry as more and more black-box warnings are issued by the FDA, and how the molecular diagnostic companies are crossing the hardware and software incompatibilities of the system platforms.

Writing in the journal of business biotechnology, "will personalized medicine be a driver of widespread price control?"

 

The research and analysis report of Chinese molecular diagnostic reagent industry (2012) analyzed the American molecular diagnostic industry cluster.

First of all, the United States has strong basic research, strong support of venture capital, strong promotion by local institutions and extensive use of information technology. The United States has five leading biotechnology industrial zones in the world.

Second, local governments are ahead of their time.

Third, there are the advantages of information technology and biotechnology integration.

Finally, American capital advantage, entrepreneurial culture and human culture.

The international federation of personalized medicine is an international organization of personalized medicine.

 

The spring 2013 issue of the international federation of personalized medicine offers a detailed analysis of the field of molecular diagnostics in the United States, where patient-oriented personalized medicine is growing strongly, creating a broad and promising industry.

Many scientists, government officials, NGO members and entrepreneurs are passionately involved.

But in the aspect of personalized medicine, relevant laws and regulations lag behind.

Therefore, the development of personalized medicine needs to be reformed.

As the leader of individualized medicine in the United States, the federation of individualized medicine (PMC) collects enough cases to consolidate the compensation act, vigorously promotes the development of individualized medical education, and encourages decision-makers at all levels of government to change the status quo and accept individualized medicine.

 

American scholar hogan, in conjunction with a law firm, analyzed the relevant laws and regulations of personalized medicine (mainly involving the FDA and CMS) and wrote the article "the development path of personalized medicine regulation (in vitro) diagnosis market".

This paper discusses the role of personalized medicine in the medical process, how to use the knowledge of personalized medicine to diagnose and treat patients, and how to deal with special cases.

But America's policy environment now gives doctors a comfortable working environment, so while they know the benefits of personalised medicine, few have much incentive to change.

In this context, the FDA is in a position to be the change maker, and it has now planned testing and development in standard personalised medicine laboratories.

 

The book 2013: the year of diagnosis considers that 2013 is the year of molecular diagnosis, and describes the development strategies of more than a dozen molecular diagnosis companies, and analyzes how the trade protection policy finds a foothold for enterprise molecular diagnosis products.

Ratner et al. published how to build a molecular (cytotoxic) diagnostic company by studying several American molecular diagnostic companies.

Eric published the article "breaking the routine: personalized medicine for environmental governance", further exploring the possible application of molecular diagnosis in environmental governance [12].

Marketline conducted a SWOT analysis of Myriad Genetics, America's largest molecule, in 2012 and 2014.

 

According to Kalorama Information's authoritative market report, "China clinical diagnostics - market analysis and manufacturer's catalog (2008)," growth in the U.S. was below 10% in 2003-2008, while China's cagr was 16%.

According to the market research report of Frost & Sullivan, from 2008 to 2012, China's clinical in vitro diagnosis market grew by more than 18%.

The single nucleotide polymorphism (SNP) -based molecular diagnostics industry is growing at an incredible 30%.

Per capita in vitro diagnosis (in vitro diagnosis market size/population) in China is about 2 us dollars, compared with the average us $30.

 

Overview of molecular diagnostic research in China

 

China's molecular diagnostic technology started relatively late. Due to the genetic differences between eastern and western RACES, as well as the differences in pricing mechanism and medical structure, it is difficult for foreign companies to enter the Chinese market, and their prices are much higher than those of domestic products.

On the whole, the growth of the domestic market is driven by the potential demand released by national policies.

Although great progress has been made in the study of personalized medicine in Chinese population, scientists and medical workers have provided a lot of clinical data to prove that the metabolism of multiple drugs is related to the polymorphism of multiple genes.

However, the development of laboratory medicine in China has been lagging behind the United States for a long time, with fewer projects, less than 10% of that in the United States, low scale and lack of standardization, very immature quality control, and certain limitations in the regulatory system, which has greatly hindered the industrialization of clinical diagnostic reagents in China.

 

In 2003, zhang zheng, zhao chunjiang and zhu qingyi compared molecular diagnostic techniques from the aspects of medicine, genetics and biotechnology, but they were all limited to methodology.

Yang Zhong in 2004, with the method of information science and soft science, system research of in vitro diagnostic reagents and market access management at home and abroad, analyze the characteristics and the factors affecting the quality of in vitro diagnostic reagents, according to "system, scientific, necessary and feasible evaluation index system design principles, through expert consultation, set up in order to" safety, accuracy, stability and diagnostic value of first-level indicators, containing 10 secondary indexes of in vitro diagnostic reagents technical evaluation index system.

On the basis of expert consultation, through the comparison of the weight calculation methods, the rank sum ratio method is used to determine the weight of each index, and the fuzzy comprehensive evaluation method is used to carry out the trial evaluation verification.

 

In 2005, lu jianxin published the application prospect of molecular diagnostics in laboratory medicine, pointing out that many molecular diagnostic methods have been established in various laboratories in China, some of which have been applied in clinical practice, but the methods are not mature and stable enough, and there is a lack of methodological comparison, so it is difficult to provide accurate information for clinical practice.

In recent years, relevant departments have begun to manage the detection of nucleic acid of pathogenic microorganisms in infectious diseases, but it has not been involved in the detection of pathogenic genes.

Therefore, it is urgent to develop the standardization and supervision system of molecular diagnosis as soon as possible.

 

According to WHO, 10-20% of Chinese patients suffer from adverse drug reactions.

Zhu bin made a comparative study on various methods of molecular diagnosis, and published several articles on the research of gene detection methods and the management of molecular diagnosis enterprises. He introduced the concept of personalized medicine into China and developed gene chip detection kit.

In 2009, China food and drug administration (CFDA) gave him the first gene diagnosis kit product registration certificate (CYP2C19).

In 2012, many foreign companies entered China's third-party medical diagnosis market.

 

Fu weiling focused on individual medicine and reiterated that the number of hospital admissions due to adverse drug reactions in China was as high as 2.5 million/year and the number of deaths reached 200,000 / year.

The results of pharmacogenetics and pharmacogenomics indicate that the genetic variation of the genes encoding drug metabolism related enzymes, drug binding related receptors, drug transport related membrane channels, and signaling related proteins is closely related to drug adverse reactions.

Taking CYP2C19 and EGFR as examples, the current status of relevant molecular diagnosis projects in personalized medicine was expounded, and the development of personalized medical molecular diagnosis in the field of laboratory medicine was predicted.

 

In 2010, xu weiwen summarized the establishment and significance of common technical indicators for the development of in vitro diagnostic reagents by integrating laws, regulations and experimental technologies.

In 2011, hu litao and wang wei of Peking union medical college hospital and wang guoguo of the ministry of health analyzed the challenges facing clinical molecular diagnosis and concluded that all genetic tests and most molecular tests should comply with CllA's regulations on highly complex diagnostic tests.

Molecular diagnostic quality control methods need to be developed over a longer period of time, and IVD manufacturers and clinical laboratories work together to improve the quality control methods of molecular diagnosis.