Deng Zixin, academician of the Chinese Academy of Sciences: Changing the path of traditional drug discovery, synthetic biology is accelerating

21st Century Business Herald reporter Wu Yinggang Hainan Boao reported "Today's medicine, pharmacy, and even physics, chemistry, computer, information science and engineering science and technology can be associated with biology, which will become a huge engine for the agglomeration development of life sciences, providing a huge driving force, and the final result of integration is the birth of a new discipline, the 'third biotechnology revolution' - synthetic biology." Recently, at the 16th CIPEM - China Health Industry (International) Ecology Conference, Deng Zixin, academician of the Chinese Academy of Sciences and honorary dean of the School of Life Science and Technology of Shanghai Jiao Tong University, said in a keynote speech.

Deng Zixin pointed out that synthetic biology is like building a house, according to clear needs, learn from the experience of predecessors, comprehensively consider the function of each room, prepare materials, construction, decoration according to the designed blueprint, and carry out targeted restoration, transformation or upgrading if necessary.

It is understood that synthetic biology refers to the targeted design, transformation and even resynthesis of organisms to achieve the production and manufacturing methods of processing and synthesis with synthetic organisms as tools.

Based on modern biology, chemistry, molecular and cellular biology, evolutionary systematics, mathematics, physics, computer and engineering, informatics, etc., synthetic biology has made remarkable achievements in many fields such as biomedicine, bioenergy, biomaterials, medical technology and exploration of life laws.

According to McKinsey, the economic value of synthetic biology and biomanufacturing is expected to reach $100 billion by 2025, and 60% of the world's material production in the future can be achieved through biomanufacturing. It is estimated that in 2030-2040, synthetic biology will bring an annual economic value of $1.8 to $3.6 trillion.

According to data released by DeepTech, as of 2021, the size of China's synthetic biology market was about $6.416 billion, an increase of $3.938 billion over 2020.

Focus on the unknown 90%

In the speech, Deng Zixin pointed out that natural screening is the traditional path of drug discovery, for example, microorganisms and plants are the source of many important natural medicines and other large health products, and the discovery and production path of most drugs is to find an active molecule produced by organisms, determine the chemical structure, and then mutagenic primitive organisms to achieve mass production through fermentation.

This system is still used today, but in the production process, there will be problems such as difficult extraction and purification, low yield yield, waste of resources, pollution of the environment, etc., in addition, although a lot of drugs have been discovered and used, but in fact still can not face the disease "crisis" trouble, like SARS, avian influenza, Ebola and the recent new coronavirus, because it takes a long time to find a new drug from microorganisms, and the use of drugs needs to be constantly updated to fight the resistance of pathogenic bacteria.

Faced with this dilemma, according to Deng Zixin, scientists' tentacles began to focus on extreme environments, such as mining new microbial resources thousands of meters deep in the ocean, because organisms in extreme environments may produce new drug molecules that have not yet been discovered by humans. For example, Wuhan University recently discovered a compound from fungal resources that symbiosis with mangroves in the ocean, which may be more effective than paclitaxel for triple-negative breast cancer.

"But the discovery of these drugs is still a drop in the ocean and the tip of the iceberg in the entire microbial metabolism industry, and the potential of microbial metabolism is far from being released to the maximum." Deng Zixin said that a microorganism may have dozens of biosynthesis-related gene clusters, if you can find these gene clusters, it means that you may find dozens of drug candidate compounds, but now there are often only one or two known and used, the deep mining of these large number of recessive gene clusters is the hope project for the future discovery of new drugs, many laboratories around the world are focusing on this unknown more than 90% of resources, synthetic biology brings such an opportunity.

Deng Zixin pointed out that at present, it is possible to associate the relationship between genes and compound structures, which originally relied on sample screening, and now it can be used to efficiently express these recessive gene clusters by creating an efficient chassis, and even systematically mining environmental DNA (eDNA) of unknown biological sources to express various products, thereby promoting the discovery of new drug candidate compounds, and discovering the gene clusters corresponding to these compounds, thereby improving gene mutagenesis, rearrangement, recombination, etc., so that it can achieve the purpose of industrial production.

According to Deng Zixin, synthetic biology has entered a stage of rapid development, and the technological development of molecular biology, omics, bioinformatics, structural biology and other aspects is driving synthetic biology into the fast lane of rapid development.

Among them, metabolic engineering and combinatorial biosynthesis are an important basis for synthetic biology in the biological metabolism industry, for example, humans have long found that the synthetic genes corresponding to antibiotics are arranged in clusters, forming gene clusters, including structural genes, regulatory genes, resistance genes, etc., which makes follow-up research relatively easy, "Now we can do a lot of things that were previously unimaginable." ”

"Just as we can now conduct integrated research on the same class of antibiotics produced by different strains, find the mechanism of commonality and regularity of biosynthesis between them, and in order to achieve a certain function, a genome is removed and replaced with another antibiotic component." It can also be a variety of different types of compounds, different arrangements and combinations, so that the new drug design is like a puzzle, the gene is designed in a chassis cell, to achieve batch synthesis of drugs, just like from nicomomycin and polyoxymycin respectively, you can get a series of compounds, these are patented products. Deng Zixin said.

It is understood that there are two approaches to synthetic biology: one is top-down, including the use of metabolic and genetic engineering techniques to give living cells new functions; One is to directly create new biological components from the bottom up, and form more complex biological systems by building components, until artificial cells and artificial multicellular life forms are created.

Deng Zixin further said that chemists can modify the structure of antibiotics through chemical semi-synthetic methods, while synthetic biologists can find many strains that synthesize a certain class of compounds, conduct integrated research on the biosynthetic pathways of the same class of antibiotics produced by different strains, and find the mechanism of commonality and regularity of synthesis between them.

For example, the synthesis of antibiotics such as gentamicin, kanamycin and apramycin without exception forms multiple parallel pathways due to the plasticity of a gene recognition substrate, and synthetic biologists can use this parallel pathway to combine different parts of antibiotic genes and lead to different parallel synthesis pathways in cells, and new drug derivatives with new functions can be developed based on old drugs. Derivatives of similar compounds are then found by reprogramming gene clusters, for example, by gentamicin, kanamycin reprogramming.

"Just like after the combination of gentamicin and kanamycin, the new structure is named gentamicin or gentamicin, and the same can be genimycin or prakamycin and so on. These new drug compounds may have new properties and effects, such as greater activity, lower required doses, weaker toxic side effects, and greatly reduced drug resistance. These are based on the understanding of the molecular level of biosynthetic genes, which allows synthetic biologists to modify the structure, and today's disciplinary integration, technology convergence and concept improvement are constantly giving rise to new opportunities. Deng Zixin pointed out.

The industry is widely used and the market is developing rapidly

At present, the domestic synthetic biology industry is developing rapidly, according to the 2022 China synthetic biology green application and industry perception research group combing, in 2021, synthetic biology industry has become one of the hottest tracks in the investment market, according to public information, in 2021 China synthetic biology obtained 16 investment and financing, an increase of 10 cases over 2020, obtained 2.295 billion yuan of financing, an increase of 136 million yuan over 2020.

By 2022, the financing frequency and amount of synthetic biology enterprises will reach a new high, according to the incomplete statistics of the above research group, the financing frequency of Chinese synthetic biology enterprises has reached at least 43 in 2022, and the financing amount has exceeded 6.6 billion yuan, setting a new financing record.

From the perspective of financing use, the financing of enterprises is mainly used for the research and development of pharmaceutical and health products, fine chemicals, alternative proteins, beauty functional ingredients and other products, and also for the research and development of large-scale and industrial production of bulk commodities.

By 2023, according to Xiong Yan, a researcher at the Shanghai Institute of Nutrition and Health of the Chinese Academy of Sciences, global synthetic biology investment and financing showed a downward trend, and in the first quarter of 2023, global startups in the field of synthetic biology raised about $2.8 billion, the lowest quarter in the same period in the past three years, which reflects the rational and precise path of investment.

Deng Zixin said that the industrial application range of synthetic biology is very wide, and artemisinin is a classic case. It is understood that the use of artificial yeast cell synthetic biology method to produce artemisinic acid, the raw material for antimalarial drugs, directly replaces artemisinin extracted from natural plants, greatly reduces the cost, has a stable and ideal low price advantage, can produce enough quantity to treat 3~500 million malaria infection cases per year, is one of the most successful industrialization cases in the field of synthetic biology.

In addition, according to Deng Zixin's introduction, a Hubei enterprise that produces vitamin E through synthetic biotechnology intermediates has increased its output value tenfold in one year, becoming the only manufacturer in the world that uses synthetic biological intermediates to produce vitamin E, realizing the leap of vitamin E advanced and complete industrial chain in one fell swoop, filling the gap of economic safety, simplicity and efficiency, and green environmental protection in the global vitamin E industry.

In addition to the above applications, since synthetic biology breaks through the bottleneck of natural drug discovery, more natural medicines and analogues can be generated by designing new biosynthetic pathways. It can also be used to develop rapid and sensitive diagnostic reagents and in vitro diagnostic systems to meet the needs of early screening, clinical diagnosis, efficacy evaluation, treatment prognosis, and birth defect diagnosis; The integration of synthetic biology principles with semiconductor technology and the development of nanodrug delivery will provide diversified strategies for efficient and precise treatment of tumors, diabetes and other diseases.

The above research group further pointed out that the medical and health industry is the most important field of synthetic biology, covering upstream, midstream and downstream, including cell immunotherapy, medical consumables, in vitro testing, drug ingredient production, and pharmaceutical enzymes.

For example, in the field of cell immunotherapy, various types of cell therapies such as chimeric antigen receptor T cells, T cell receptor genetically engineered T cells, tumor infiltrating lymphocytes, and chimeric antigen receptor NK cells are blooming. The rapid research and development of new crown vaccines can also be seen in the credit of synthetic biology technology.

From this point of view, the subversive changes brought about by synthetic biology have been or are being staged in many fields.

However, at the same time of rapid development, in Deng Zixin's view, China's original innovative technology has developed rapidly in recent years, but there are still relatively few unique technologies, especially in terms of application, such as gene editing using foreign technology, although it is not restricted today, but if the future China's industry develops and grows, whether it will be restricted is still unknown.

Deng Zixin further said that the current application prospects of synthetic biology in the commercial field have attracted great attention and funding from countries around the world, especially the United States and Britain, correspondingly, the United States and Britain are in the leading position in the world in both synthetic biology research and application, compared with it, the gap between the mainland is still very obvious. The situation is pressing, the challenges are pressing, and the mission is pressing.

But Deng Zixin also pointed out that synthetic biology is on the rise and is subverting the research and development path of traditional health products, and can now become more active, and then produce disruptive innovation. "All in all, biologists and engineers are merging to see that synthetic biology is an engineering, biophysical discipline that rewires and programs organisms, and if it's still in infancy or early childhood today, it may not be a few years before it reaches adulthood."

"Synthetic biology may propel an industry to take off, provide green energy for cars, provide us with healthy food, advance cancer diagnosis and treatment, help solve major medical problems, and believe that synthetic biology can eventually change our lives." Deng Zixin said.

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