The mid-20th century was the golden age of natural product discovery. Scientists discovered groundbreaking drugs, like penicillin and tetracycline, from sources in nature.

But as the search for natural products continued, pharmaceutical companies kept finding the same products over and over again. By the early 2000s, most of these companies shut down their natural product discovery programs.

At the same time, the era of genomics emerged. Instead of looking for natural products, scientists were now able to use genetic information to understand how natural products were made. This brought success in discovering new natural products, but only on a very small scale.

Now, a new project aims to discover new natural products on a large scale by using synthetic biology and automation.

The project, funded by a grant from the National Institutes of Health, will be led by chemical and biomolecular engineering professor Huimin Zhao and chemistry professors Wilfred van der Donk and Doug Mitchell.

Mitchell and van der Donk, both members of IGB’s Mining Microbial Genomes (MMG) theme, will combine their expertise in natural product discovery with Zhao’s synthetic biology expertise as leader of IGB’s Biosystems Design theme. Zhao is also a member in the CABBI and MMG themes.

This interdisciplinary effort will allow them to unlock the potential of a specific class of natural products known as ribosomally synthesized and post-translationally modified peptides, or RiPPs.

RiPPs have garnered scientific interest in recent years. They’re especially promising because they’re gene-encoded, which allows researchers to quickly see what kind of useful compounds they could create.

Zhao, van der Donk, and Mitchell’s labs have been studying RiPPs for several years, and have realized that they are far more numerous than scientists originally thought.

“It’s really opened people’s eyes to how prolific and pervasive these are,” Mitchell said. “We see that there’s not just a few hundred of these, but there’s tens of thousands of them, if not more.”

Their labs have transferred the biological pathways from RiPPs into “friendly” organisms, like E. coli or yeast, to build new molecules.

“You can take a package of genes from one organism, stick it in another organism, perhaps optimize it a little bit, and make the molecule in the friendly organism,” van der Donk said.

However, they’ve only been able to do this on a small scale, building a handful of molecules at a time. Now, they want to do this on a large scale — building hundreds of molecules at a time — using an automated robotic system and synthetic biology tools developed by Zhao’s lab.

The robotic system, called iBioFAB, will not only allow them to identify new RiPPs and create new molecules, but also determine — to some extent — whether they have medical value.  

“We think that we can now unleash them for the first time by creating a broad-scale pipeline for not only finding them in genomes, but actually producing them and getting them screened for activity,” Mitchell said.

Their goal is to discover a thousand new RiPP compounds, a target that hasn’t been reached before.

While they may be able to determine the medical value of these compounds, their main goal is to discover new natural products and see what’s out there. To some extent, they’re unsure of what they’ll find — a potential disadvantage that’s reminiscent of natural product discovery efforts in the mid-20th century.

“They would just take soil samples,” van der Donk said. “They had no idea what was going to be in the soil samples, but it turned out that most of our current antibiotics were found that way.”

Because their automated method will allow them to identify a large number of molecules at a time, the chances they’ll find several interesting compounds are high.

“Even if you’re 5 percent successful, you’re going to be inundated with lots of cool-looking new molecules,” Mitchell said.

For Zhao, this project is a step toward his goal of building an international team of scientists dedicated to natural product discovery. With this kind of effort, Zhao imagines finding not just thousands, but tens of thousands or even millions of new natural products.

“In principle, we can discover all the natural products that nature produces,” Zhao said. “That’s my dream, but with joint and coordinated efforts around the world, this dream is not entirely unrealistic.”

The lifesaving drugs that the pharmaceutical industry developed from natural products have added more than a decade to the human lifespan. And this industry, according to Mitchell, is built on just one percent of the chemical bounty of the microbial world.

“If that’s added decades to the human lifespan,” Mitchell said, “what could happen if we actually tapped that resource effectively?”