The future of all living things is promising | A side note on the pioneer of synthetic biology research (4) Researcher Qiao Xue: using "natural product Lego" to re understand the synthesis of traditional Chinese medicine chemical components

But 'soil' does not mean conservatism. Long term research on the complex system of traditional Chinese medicine has made her aware of the limitations of traditional research methods. When pharmacological experiments require gram level candidate molecules and the content in medicinal materials is extremely low, traditional extraction and separation methods will face huge challenges. This bottleneck prompted her to turn to synthetic biology——Not relying on medicinal herbs, but using microorganisms to 'grow' the effective ingredients of traditional Chinese medicine.

This road was not easy, but it allowed her to find a new language to tell the story of traditional Chinese medicine.

Qiao Xue's research started with the analysis of chemical components in traditional Chinese medicine. Due to the high complexity of traditional Chinese medicine ingredients, the research team has long relied on liquid chromatography (LC) and liquid chromatography-mass spectrometry (LC/MS) for analysis. But analysis can only 'see' and cannot 'get'. When pharmacology or clinical research requires sufficient amounts of compounds, the problem arises. Relying solely on liquid chromatography-mass spectrometry cannot obtain the target compound, and even with large-scale preparation liquid phases, it is limited by the natural content of target components in medicinal materials, which will consume a large amount of traditional Chinese medicine resources and manpower.

It was this "visible but unattainable" dilemma that prompted her to turn to biosynthetic research in 2015. The research team has shifted from "analyzing traditional Chinese medicine" to "synthesizing traditional Chinese medicine", gradually focusing on the biosynthetic mechanisms of plant natural products, and officially entering the field of synthetic biology.

In exploring how plants synthesize active molecules, researcher Qiao Xue proposed a vivid metaphor - "natural product Lego".

This idea stems from a renewed understanding of enzyme function. High school textbooks emphasize that "enzymes have specificity, one key unlocks one lock", but practical research has found that many enzymes have "promiscuity" - the ability to flexibly catalyze different substrate combinations. For example, an enzyme can connect A with B, A with C, and even continue to connect D on the basis of AB. "Nature endows proteins with strong creativity. ”Qiao Xue said.

There are a large number of universal "building blocks" in nature, such as glucose, cinnamic acid, acetyl CoA, etc. These small molecules are widely distributed and can be flexibly assembled into diverse natural products by enzymes as "building blocks". The name "LEGO" is derived from its modular and composable nature. This characteristic opens up the possibility of constructing "non natural natural products" - retaining the natural skeleton while introducing non natural modifications to explore better pharmacological activity.

Researcher Qiao Xue pointed out that such achievements can be used for the development of natural medicines on the one hand, and on the other hand, have significant implications for the protection of traditional Chinese medicine resources: nearly half of China's commonly used traditional Chinese medicines rely on wild collection. If key components can be produced through fermentation, it will significantly reduce the consumption of wild resources. In addition, enzymes and regulatory factors discovered in biosynthesis research can also be used in molecular breeding to help select high-quality medicinal plant sources.

Clarifying the biosynthetic enzymes of traditional Chinese medicine components is technically challenging. Many plant genomes are larger than humans, and identifying target genes is like finding a needle in a haystack. "Qiao Xue's team is skilled in using the" correlation analysis "strategy: by perturbing plants, observing synchronous changes in target compounds, intermediates, and gene expression levels, and narrowing down the candidate range. This strategy heavily relies on precise analysis and testing techniques.In terms of instrument selection, the research team chose liquid chromatography and liquid chromatography-mass spectrometry as the preferred solutions, and their understanding of many commonly used traditional Chinese medicine ingredients was based on Agilent LC/Q-TOF and 2D-LC/MS instruments.

Researcher Qiao Xue admitted that her decision to engage in scientific research was not deliberate, but a natural choice. This is thanks to the support of her teachers - Professor Guo De'an and Professor Ye Min's profound accumulation and persistence in the field of traditional Chinese medicine have deeply influenced her. Scientific research is an interesting thing, and if you choose to do it, you must do it well. When cultivating her students, she always strives to create a free and open research atmosphere, encouraging them to step out of their comfort zone and maintain curiosity about new things and technologies. During the experimental process, students' intelligence, diligence, and perseverance are important driving forces for the continuous advancement of the project.

Qiao Xue's research also relies heavily on the valuable support of the author, peers, and Agilent technical experts. Their constructive suggestions put forward in multiple exchanges have provided important inspiration for the advancement of the project, for which she is deeply grateful.