Have you played Lego before? No matter how sophisticated our Lego-constructions are, Nature always beats us at it, especially when it comes to the medicine. Lihan Zhang, a principle investigator at School of Science of Westlake University is playing the game. Leading the Natural Product Bioengineering Lab, Zhang and his team aim at deciphering how Mother Nature produces active natural products that can be used for medicine and uncovering more useful ones.

“Nearly half of the drugs that we use are based on natural compounds. We can better develop drugs by learning the mechanism of natural production,” said Zhang. 

Zhang’s lab is home to numerous Streptomyces, a very smart group of bacteria. “They can produce and stimulate many useful compounds under different cultivating environments, including our key research subject, polyketides,” said Zhang. Polyketide is a very potent class of natural products widely used in medicines. In Streptomyces, these polyketide compounds are synthesized by an enzyme called polyketide synthases. 

It’s been 25 years since we discovered polyketide synthases, but the cause for its potency remains a myth. Zhang explained, "polyketide synthases can run three to four different chemical reactions, each producing its own compounds, and connect them together in a ‘assembly line’ manner to form natural products. We are yet to understand how this assembly is precisely regulated.”

The interdisciplinary development helps to tackle this challenge. “In the past, we could only research on one enzyme at a time. Thanks to big data and genetic profiling, we now have the capability to process massive data. This allows us to analyze the gene sequences of different enzymes and compare how they produce different natural compounds and design ‘new natural assembly lines’”.

In the meantime, Zhang’s team is also working on understanding the diversity of natural compounds. “Not all the genes participate in the process of compound synthesis. We are also studying the genes of enzymes in hope of learning how the biosynthetic enzymes coordinate together,” said Zhang. 

“It is an interesting time to study natural products. New technologies bring along new possibilities.” Looking ahead, Zhang wishes to crack more mysteries of natural compounds. 

Lihan Zhang was born in Jilin province. His family moved to Japan when he was 4 years old, where he later received his bachelor’s, master’s and doctoral degree in pharmaceutical sciences at The Univeersity of Tokyo  . Zhang completed his postdoc research at Harvard University and when he was looking for job opportunities he found out a brand-new university called Westlake University. “I found this novel institution to be highly international, research-oriented, and collaborative between researchers.” Zhang joined Westlake University as a full-time researcher in September 2019.

Fascinated by natural products, Zhang is aiming to expand his research interest to the evolution and bioengineering. “My postdoc research focused on the activity and biosynthetic mechanism of natural compounds, and now my focus is shifting to designing and producing new natural compounds that we want to get.” Currently, there are six members in his team, each coming from a different academic background.

Zhang runs a “low” threshold when it comes to recruitment, “I want my students to have a strong interest and curiosity in scientific research, and the ability to think in-depth and critically.” In terms of academic background, he said, “chemistry is the core to understand natural products, but they can learn it after joining my team."