For his innovative research of natural products, Associate Professor Jason Kwan is being nationally recognized by the American Society of Pharmacognosy

By Aarti Gupta

Natural products, also known as secondary metabolites, are small, bioactive molecules made by living things. They are products of evolution — researchers believe that there is a selective advantage for their creation, such as defense from predators or pathogens, suppressed growth of rivals, or increased communication.

Jason Kwan, associate professor in the University of Wisconsin–Madison School of Pharmacy’s Pharmaceutical Sciences Division, is captivated by these molecules. The Kwan Lab aims to not only discover new natural products, but also to understand why they are made, their role in symbiotic relationships, and how they can be applied to advance drug discovery and therapies.

“I’m typically hyper-focused on finding out interesting things about uncultured bacteria and natural pathways,” says Kwan. “Anything that’s kind of an interesting or weird system is really fascinating to me.”

“His work is giving us a better understanding of evolution in the context of symbiosis and specialized metabolites.”
—Tim Bugni

Kwan’s passion for these molecules have led him to his latest honor: the 2023 American Society of Pharmacognosy’s (ASP) Matt Suffness Young Investigators Symposium Award, which recognizes new and upcoming researchers who have excelled in their contributions to natural product research.

“It felt great to have won,” Kwan says. “It is gratifying that those who nominated me and ASP felt that I was worthy of the award.”

Harnessing evolution

Kwan was nominated for the award by Marcy Balunas, associate professor at the University of Michigan;  Tim Bugni, professor in UW–Madison School of Pharmacy’s Pharmaceutical Sciences Division; Eric Schmidt, professor at the University of Utah; and Kerry McPhail, professor at Oregon State University. 

Bugni, who also researches marine natural products, has collaborated with Kwan since Kwan joined the School of Pharmacy in 2013. He describes how interesting and impactful Kwan’s research is.

“Jason has tackled big, challenging problems,” Bugni says. “From my perspective, it’s clear he’s at the top of the field. He’s answering some really cool, important questions, and his work is giving us a better understanding of evolution in the context of symbiosis and specialized metabolites.”

Kwan’s research began in natural products isolation — simply discovering new molecules and understanding their structures. Over time, he became more interested in why natural products were produced in the environment, and during his post-doc, he worked in Schmidt’s lab to manually assemble the sequences from one symbiont within a microbiome that has sequences from the host and other bacteria present — a process known as binning.

“As I began my independent career, I sought to develop more automated methods of binning, with the goal of being able to examine hugely complex microbiomes,” says Kwan. “I work to make computer programs that separate metagenomes and individual genomes, and I also find different ways to mine sequence data.”

In his latest feat, Kwan is working to advance his sequencing systems by completing manual analysis of horizontally-transferred biosynthetic pathways.

“Bacteria of different species can actually transfer DNA in between them,” he says. “This is one of the reasons why antibiotic resistance travels so fast when you start using antibiotics. Each individual species doesn’t have to independently evolve antibiotic resistance — once it has evolved, it can be shared between species.”

Bacteria also share biosynthetic pathways for natural products, so they can transmit the ability to make antibiotics, as well as to be resistant to them.

“We found several examples of symbionts that have these biosynthetic pathways. And you can tell they’ve been horizontally transferred, because the balance of nucleotides are different for the main genome and the pathway,” he says. Because of these discrepancies, algorithms will often put the pathway in the wrong genome, so Kwan and colleagues manually review data to make sure the genomes have been correctly separated.

“If it’s that different in terms of nucleotide composition, that suggests the pathway has been recently transferred in, and there are lots of cases we found multiple copies of the same pathway, which suggests that the evolutionary pressure to have those genes around is much higher,” says Kwan. “When we do our manual analysis, we feed it back into the software to make the algorithm better next time.”

Bugni notes how influential Kwan’s development of sequencing tools, such as his lab’s Autometa, has the potential to be. 

“I think the biggest area of impact Jason has is developing tools to assemble DNA collected from an environment into a genome,” says Bugni. “While his applications have primarily been in the marine area, they can be applied to any system: human, marine sponge, insect, and more. Being able to get a view of the organisms in any environmental niche is going to impact a lot of science.”

Kwan is also interested in the therapeutic applications of natural products. He hopes to be able to utilize these compounds to produce therapies that effectively treat a large range of human illnesses and conditions.

“For instance, a species may produce something poisonous in order to stop predators from eating it, but that same product, in the correct dosage, could have the potential to kill cancer cells in the human body,” he says.

In other example, one of Kwan’s most prominent projects involves looking at an antifungal microbe found on the eggs of the Lagria villosa beetle, which protects the eggs from soil-based fungal pathogens.

“There are also lots of compounds that bacteria produce to compete with other bacteria in the environment, which we can use to expand antibiotic treatment for some bacterial infections,” he says. 

Leading the field

Kwan’s work has not gone unnoticed. Kwan has been the recipient of several awards, including the National Science Foundation CAREER Award and the R35 Maximizing Investigators’ Research Award (MIRA) from the National Institute of General Medical Science. The CAREER Award has supported Kwan as he works to develop new bioinformatic approaches to metagenomic sequencing, while the R35 MIRA Award has enabled Kwan’s application of natural products to treat conditions such as bacterial infections and cancer.

“Bacteria of different species can actually transfer DNA in between them. This is one of the reasons why antibiotic resistance travels so fast when you start using antibiotics.”
—Jason Kwan

While these projects keep him busy, over time, Kwan wants to spend more time thinking about the big picture: culturing the producers of natural products. While it won’t be easy, Kwan wants to bridge the gap between discovering the genes that make up a natural product and making them expressed and applicable in the lab.

“It has been a goal of mine to be able to take enzymes, fit them together, and make a huge pathway of natural products from scratch,” Kwan says. “The infuriating thing is that evolution has been able to use millions of years and different environments to select for certain traits, so it may be out of the grasp of humans. But we have to try.”