Scientists have developed a powerful gene-editing tool that activates dormant drug-producing genes inside fungi, uncovering previously hidden natural compounds with promising anti-cancer activity. This breakthrough could lead to future medicines. The research, led by the School of Engineering and Applied Science and published in Nature Biotechnology, shines a spotlight on a kingdom of life that has long remained overlooked despite giving the world life-saving drugs such as penicillin and cholesterol-lowering statins.

"Researchers have spent decades—and billions of dollars—sequencing animal and crop genomes, but fungi have historically been the forgotten middle child of genomics," the study noted, even though fungi have transformed modern medicine.

"This neglect is kind of remarkable considering how fungi have shaped modern medicine," said chemical and biomolecular engineer Xue "Sherry" Gao. "From the serendipitous discovery of penicillin to cholesterol-lowering statins, we owe many recent breakthroughs in longevity to fungal chemistry. But despite this, the vast majority of the fungal kingdom remains a black box."

Fungi naturally produce chemicals to defend themselves against bacteria and other microbes. However, when grown in sterile laboratories, many of the genes responsible for making these compounds become inactive, making potentially valuable medicines impossible to detect. Gao stated, "We required a powerful method to precisely manipulate fungal genomes, such as editing their master regulatory genes, but traditional tools were inadequate."

After months of laboratory work refining genetic instructions that could survive inside fungal cells, the team developed fPE7max, a precise genome-editing platform designed for filamentous fungi such as Aspergillus and Penicillium. Unlike conventional CRISPR methods, which cut both strands of DNA and may introduce unintended changes, the new approach rewrites selected genetic code more accurately without making those breaks.

Using the tool, researchers activated previously silent gene clusters and isolated 18 complex molecules, including eight never before described by science. "We isolated 18 distinct complex molecules, eight of which possessed chemical structures entirely new to science," said first author Chunxiao Sun. "Of these uncovered molecules, three exhibited promising anti-cancer properties. These molecules can serve as lead compounds for disease treatment, providing a vital new pipeline for drug discovery." One newly discovered molecule showed selective activity against laboratory-grown breast, liver and blood-cancer cells.

The platform was able to edit genes with nearly 90% success, enabling scientists to accurately change a key gene called laeA, which regulates many chemical processes in fungi. Although the findings remain at an early laboratory stage and require extensive testing before any treatment reaches patients, they strengthen growing scientific efforts to mine nature for new medicines as cancer and antimicrobial resistance continue to challenge global health. "It's a compelling proof-of-concept demonstrating that the next generation of life-saving therapeutics might already exist in nature," Gao added.