Biomedical papers-the application of synthetic biology in medicine
Abstract of biomedical papers
Abstract: Synthetic biology is to plan and transform the natural biological system from scratch under the guidance of engineering theory. And plans to manufacture new biological components, models and systems at the same time. Synthetic biology is a new discipline formed by the development of natural science to a certain extent, and has made remarkable achievements in medicine. In this paper, the research progress of antimalarial drug precursor artemisinin, anticancer drug precursor taxadiene and the methods of producing fatty alcohols, acids and higher alcohols in project cells by using synthetic biology are comprehensively described. In addition, some key synthetic biology related measures have greatly accelerated the recombination and evolution of engineering cells, providing convenient and applicable things for new utility cells used in the field of building manufacturing.
Catalogue of biomedical papers
Keywords: synthetic biology; Gene module; medical science
introduce
In recent years, the development speed of synthetic biology has been greatly improved, and the exploration essence and application category with obvious characteristics have been gradually created. The key to its exploration and implementation includes: (1) planning and construction of new biological elements, components and systems. (2) Re-planning the existing natural biological system. In 2009, an IDR team consisting of 12 bachelors from all walks of life was established under the leadership of the American Department of Medicine to study the direction and interdisciplinary situation of synthetic biology. It is considered that synthetic biology is an interdisciplinary subject integrating computer, physics, engineering and biology, and can be applied to environment, medicine, people's health, resources and other parts through reorganization.
Synthetic biology is formed by the progress of engineering science and biology to a certain extent. The completion of the human genome, the determination of unknown sequences in various forms of biological genomes, and a lot of post-genome work have raised the accumulation of biological data to astronomical level. However, the existing data mining is still limited to the in-depth exploration of life characteristics, and it is difficult to explore and analyze the internal working mode of life. Synthetic biology was formed in this environment. After constructing life behavior from bottom to top, life is explained from its unique angle, which provides a foundation for rational planning and innovation of life. In recent years, unknown sequences and synthetic units for genome determination have been established worldwide, providing high-quality and low-cost services. Excellent genome determination and synthesis measures of unknown sequences promote the planning of new life combinations and the simplicity of constructing functional cells in synthetic biology.
Crucially, the huge demand of human beings for health, resources and conditions has also promoted the rapid progress of synthetic biology. The utility gene model appears when the gene components are organically recombined and integrated according to the needs of the project. In addition, using the existing biological network and introducing a new utility gene model, it shows that what natural cells can't synthesize has made great progress in the synthesis part. Now let's analyze the synthetic biology subjects used in the medical field.
Biosynthesis of 1 Artemisia annua diene
Jay. Kosslyn explored the production of artemisinin, a precursor of malaria resistance, in project cells, which is really classic. After producing important new genetic data of artesunate synthesis mode, kosslyn's team successfully studied another method of producing artesunate in Escherichia coli in 2003. This synthesis method is divided into two forms. The first one is based on acetyl coenzyme A, and IPP is generated from methyluric acid. This gets rid of the original G3P of Escherichia coli and the isoprene pyrophosphate method produced by acetylformic acid, which can make the cell metabolism form isoprene pyrophosphate molecules in a new way and provide enough substrate molecules for downstream manufacturing methods. In the second form, starting from C5 isoprene pyrophosphate, the isoprene chain is extended to form FPP of C 15, and finally artesunate is produced under the action of ADS enzyme, with the highest yield of122 mg/L. Both upstream model and downstream model are derived from the metabolic model of eukaryotes. In prokaryotic Escherichia coli, the coding was improved and transformed, and the required items were successfully manufactured, which opened up a new way to manufacture organisms.
In 2006, Keasling team took yeast as the host, up-regulated or down-regulated the key genes of endogenous acetyl-CoA pathway to FPP, and introduced exogenous modules of gene optimization, which successfully achieved a steady increase in artemisinin production. There are two ways to up-regulate endogenous genes, one is to increase the copy number of genes, such as tHMGR enzyme gene, and the other is to up-regulate gene expression through transcription factors, such as ERG series genes. Down-regulation of endogenous genes is the method of gene knockout. Through a series of fine-tuning the genes involved in the synthetic pathway, the yield reached 153mg? L- 1, which is 500 times of diene molecular output reported in the past.
On this basis, the research team designed and synthesized protein scaffold, and optimized the upstream module in E.coli: the synthetic route from acetyl-CoA to mevalonate. AtoB, HMGS and tHMGR are combined in different molecular proportions through protein scaffold, which solves the problems of reduced synthesis efficiency and toxic side effects on the host caused by the accumulation of intermediate metabolites. The specific mechanism is that the ligand-receptor interaction in higher animal cells is introduced into Escherichia coli, and the gene sequence of ligand molecules and the reactive enzyme gene in the module are fused and expressed, so that the receptor molecules are connected in a string with different molecular numbers to form a flexible scaffold. Because the receptor molecules in the scaffold are connected by a certain length of polypeptide, the steric hindrance caused by the combination of multiple ligand receptors is avoided. After repeated experiments and debugging, the research team found that the combination of the three enzyme molecules in the ratio of 1: 2: 2 was the strongest, and the output reached 77 times of the initial value, about 5mmol? I- 1(740mg？ L- 1).
With the late stage of industrial fermentation, the research team also found that the enzymes expressed by exogenous genes HMGS and tHMGR from yeast were not enough to balance exogenous metabolic flow, which became a bottleneck reaction. After they replaced the related enzyme genes of Staphylococcus aureus, the output of artesunate immediately doubled. Combined with the optimization of industrial fermentation process, the final output of artemisinin as an industrial product is as high as 27.4g? L- 1. Synthetic biology has been successfully applied to the synthesis of important drugs, which has attracted wide attention.
Biosynthesis of Taxadiene
Gregory Stephanopoulos's scientific research organization successfully synthesized taxadiene, the precursor of anticancer drug, in E.coli in 20 10. This is the result of our group's long-term exploration of terpenoid metabolism and fine regulation of Escherichia coli cells. Scientific organizations have positioned the internal synthesis mode of diisopropyl peroxydicarbonate as upstream mode, and the subsequent synthesis mode of taxadiene as downstream mode. The key operation of aggregation is how to fine-tune the upstream and downstream modes. Because if we only care about the upstream, it will definitely lead to the consumption of intermediate metabolites and form an intermediate barrier; However, if the downstream flux is too much, it will waste a lot of enzyme molecules and increase the cell expression load.
The research team fine-tuned the ratio of upstream and downstream flux by changing the copy number of plasmid and the strength of promoter. By integrating the existing literature and our own detection work, the research team determined that the copy numbers of three plasmids, pSCl0 1, p 15A and pBR322, were 5 10 and 20, respectively, while the copy number of genes integrated into the genome was equivalent to 1. The relative intensities of three promoters Trc, T5 and T7 are 1, 2 and 5 respectively. Through the combination of these plasmids and promoters, the flux ratio of upstream and downstream modules was changed, and then the product yield in cells with different flux ratios was checked. In this process, whether the genes in the module are single cis-trans or multi-cis-trans also affects the change of yield, that is, whether multiple genes are expressed after one promoter or after their respective promoters. After a series of fine-tuning and combination, the target product yield of the strain with the best characteristics is as high as (1020&; plusmn80)mg？ L- 1, which realizes the efficient utilization and coordination of carbon metabolic flow. At the same time, cytochrome P450 oxidoreductase was transformed by protein engineering and successfully expressed in engineering bacteria for the first time.
3 outlook
Guided by the principles of engineering science, synthetic biology plans and reorganizes existing and natural biological systems from scratch, and makes every effort to plan and synthesize new biological components, models and systems. Especially in the use part, the artificial biological system constructed by synthetic biology discipline can have the main room for improvement in making key biological varieties and caring for the human body. At present, the exploration results of synthetic biology are mainly used in medicine, and there will be remarkable achievements in other industries in the future. In a word, synthetic biology has universal application premise and strong measures to support it.
Research on the Development of Biomedical Industry in China
Abstract of biomedical papers
Biomedical industry consists of biotechnology industry and pharmaceutical industry. This paper analyzes the development status of biomedical industry at home and abroad, analyzes the problems existing in the development of biomedical industry, focuses on the basis and shortcomings of the development of biomedical industry, and seeks countermeasures to realize the "four modernizations" in the development process of biomedical industry and promote the rapid and stable development of biomedical industry.
Catalogue of biomedical papers
Keywords Biomedical development countermeasures
I. Development Status of Domestic Biomedical Industry
From 65438 to 0986, China officially implemented the "863 Plan", and biotechnology was listed as the first of seven high-tech fields, including aerospace and information technology. The government gives certain preferential treatment and support in the process of biotechnology research and development and industrialization development; Major domestic enterprises have invested a lot of money in biotechnology industry; China's financial sector is also actively involved in the development of biotechnology industry. Many powerful companies use the financing of financial markets to develop biotechnology and engage in biotechnology research and industrialization. At present, the world is in the initial stage of large-scale industrialization of biomedical technology, and it is expected that it will enter a period of rapid development after 2020 and gradually become one of the leading industries in the world economy.
1, supported by industrial policies, attaches great importance to the development of biomedical industry.
China government regards the biomedical industry as a strategic industry with priority development in the 2nd/Kloc-0th century, and increases policy support and capital investment for the biomedical industry. The Tenth Five-Year Plan clearly states that the focus of medicine development during the Tenth Five-Year Plan period lies in the modernization of biopharmaceuticals and traditional Chinese medicines. The state has formulated a series of supporting policies for the R&D, production and sales of biopharmaceutical products, including implementing various preferential tax policies for biopharmaceutical enterprises, extending the product protection period and providing R&D financial support. At the same time, in order to strengthen the management of the industry, the state has adopted strict examination and approval procedures for the development and production of biomedical products, and taken measures to limit the number of examination and approval projects for some biomedical products in view of the serious duplication of construction, so as to ensure the market exclusive rights of new drugs and reasonable profit returns and encourage the development of new drugs. In 2007, the National Development and Reform Commission published the Eleventh Five-Year Plan for the Development of Bio-industry, which formulated relevant policies and measures in the aspects of organization and leadership, industrial technology innovation system, talent team, investment, preferential tax policies and market environment, so as to ensure the rapid development of bio-industry, which is of great significance to the development of bio-pharmaceutical industry.
2. The process of biomedical industrialization has been obviously accelerated, and the investment scale and market scale have expanded rapidly.
Since the mid-1980s, with the strong support of national and local government policies, the biomedical industry has developed vigorously in China. According to the relevant information of the State Economic and Trade Commission, before 1998, the total investment in biomedical technology development in China was about 4 billion yuan. Since 1999, the state has obviously increased its investment in biomedicine, reaching an average of about 2 billion yuan per year. Under the influence of preferential policies related to the biomedical industry, some domestic biomedical enterprises have obtained a large amount of funds through their own funds and bank loans for the research and development of new products. At present, there are more than 600 companies, universities and research institutes engaged in the research and development of biotechnology industry and related products in China, including more than 200 registered biomedical companies and more than 60 with production capacity (48 of them have obtained the approval for trial production or production of genetically engineered drugs).
3. A pharmaceutical industrial cluster represented by Zhangjiang in Shanghai and Zhongguancun in Beijing has been initially formed.
Driven by the rapid development of biotechnology industry, after years of development and market competition, coupled with the timely guidance of the government, biomedical industrial clusters have gradually formed in areas with intensive biotechnology, talents and funds in China, thus forming a relatively complete biomedical industrial chain and industrial cluster. For example, Zhangjiang Pharmaceutical Valley Industrial Cluster consists of more than 40 first-class pharmaceutical companies at home and abroad, such as Roche, GlaxoSmithKline and Pioneer Pharmaceutical, with gene research, compound screening and new drug research and development as the core; Beijing Zhongguancun Life Science Park has Novo Nordisk Pharmaceutical Company and 8 national 863 biotechnology projects; Shenzhen Life Science Park focuses on biopharmaceuticals, especially genetic engineering pharmaceuticals. These industrial clusters have gathered a large number of institutions including biological companies, research, technology transfer centers, banks, investment and services, and initially formed industrial clusters (pharmaceutical factories), which have a good innovation and entrepreneurial environment composed of six modules: research and development, incubation and innovation, education and training, professional services and venture capital, and have made important contributions to expanding the scale of biomedical industry and enhancing industrial competitiveness.
Second, the domestic biomedical industry problems
1, the investment model is not conducive to the development of biopharmaceutical industry.
The great economic benefits of international pharmaceutical industry come from innovation. The modern biopharmaceutical industry in developed countries has its own powerful research institutions, and the annual investment usually accounts for 10%-20% of the total sales, while the investment in biopharmaceutical research and development in the United States accounts for 60% ~ 70% of the total investment. Every large pharmaceutical company has its own "fist product", and the annual sales of a single product can reach one billion to several billion yuan. The company owns the intellectual property rights of these products, and the state gives them patent protection. Production and occupation can monopolize the market for 10 years or longer, a product can win huge profits, and then huge funds are invested from the profits to develop innovative new drugs with intellectual property rights, forming a virtuous circle again and again.
From the perspective of the development model of biopharmaceuticals in the United States, the key to the healthy development of biopharmaceuticals industry is the organic combination of technological development and innovation by small expert biotechnological companies with strong technical strength, industrialization of biotechnology by large pharmaceutical companies through strategic alliances, and financial support provided by venture capital for biotechnological development. Judging from the current biopharmaceutical industry model in China, production is mainly realized by purchasing technology, with insufficient venture capital mechanism, too little capital and weak technological innovation. Therefore, it is difficult for the biotechnology industry to form a climate.
China's pharmaceutical enterprises are small and scattered, and most of them do not have the ability of technology development and innovation. The products produced are basically imitation products, and the phenomenon of repeated development investment is also very serious. Vicious competition will inevitably lead to inefficiency. China's drug imports are increasing year by year, and the product sales of foreign-funded enterprises are also increasing year by year. A foreign research report pointed out: "If the government does not intervene, China's pharmaceutical market will be completely manipulated by international pharmaceutical companies within five years."
2. Low-level repeated research and repeated construction are serious, and the market competition is fierce.
The broad prospects and rich profits of biotechnology products have attracted many domestic enterprises to develop them, but most of them are copied from abroad, with few varieties and many manufacturers, and repeated investment in construction at the same level. For example, the development of rhug &; MdashCSF has 18 companies. According to statistics, only 1996- 1998, recombinant human interleukin-2 (l & mdash; 2) There is 10, and the recombinant human erythropoietin (EPO) is above 10. This will inevitably lead to waste of resources, price suppression and market chaos. Moreover, due to the lack of product market investigation and analysis, some enterprises accumulate a large number of products, which leads to the low utilization rate of complete assembly line equipment with high investment price, and some of them have an annual utilization rate of less than one month. The price war in turn caused the quality of products to decline, and counterfeit and shoddy products flooded the market. Consumers have low trust in domestic biotechnology products and prefer to use expensive imported products.
3. The disconnection between scientific research and industry is still serious.
At home, the research purpose of scientific research institutions is to follow up the development of international advanced science and technology, and the research direction is too focused on the upstream technology development of several popular varieties, but few projects can be industrialized. In foreign countries, after the scientific research results are completed, they fall into the R&D center of the enterprise for further incubation, forming a technical process, and then mass production, which is seriously out of line in China. The lack of entrepreneurs with scientific minds and enterprises with technological development capabilities to turn research results into production has greatly hindered the development of industrialization.
4. Low market development ability.
Due to the backward production technology and management methods, the domestic market will face the impact of imported drugs. The specific manifestations are as follows: First, the efforts to open up foreign markets are not enough, and many enterprises are not well positioned in the market; Second, the investment in developing the market is insufficient; Third, although the good clinical effect of biological drugs has been affirmed by medical staff and patients, their prices are relatively high and their consumption capacity is insufficient. Therefore, China needs to further increase investment in biopharmaceutical industry and deepen the mechanism reform of industrialization of scientific research achievements. In this process, the capital market and venture capital companies should play an active role.
Three, to speed up the development of China's biomedical industry countermeasures and suggestions
The research and development of biotechnology drugs in China started late, and it was not until the early 1970s that DNA recombination technology was applied to medicine. However, the country attaches great importance to the development of biotechnology industry, and regards it as a strategic industry with priority development in the 265,438+0 century, and has increased policy support and capital investment for biomedical industry. The Outline of National Medium-and Long-Term Science and Technology Development Plan (2006-2020) issued by the State Council in 2006 pointed out that in the future 15, China will deploy a number of cutting-edge technologies in the field of biotechnology, including target discovery technology, animal and plant species and drug molecular design, gene manipulation and protein project, human tissue engineering based on stem cells and a new generation of industrial biotechnology. This deployment undoubtedly points out the direction for the development of biopharmaceuticals in China. A member of an expert group who participated in the Twelfth Five-Year Plan of the pharmaceutical industry revealed that in the special plan being formulated, the biomedical industry and industrial upgrading will become the key development directions in the next three years. The "Special Plan" takes the development and industrial upgrading of the biomedical industry as the focus of the pharmaceutical industry in the "Twelfth Five-Year Plan", and requires tracking the frontier technologies of biomedicine and occupying the commanding heights of the biomedical industry.
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