UPenn Launch Filamentous Fungi Gene-Editing Tool Unlocking Fungal Molecules With Early Anti-Cancer Promise
- Gauri Khanna
- 1 day ago
- 3 min read
Researchers at the University of Pennsylvania have developed fPE7max, a gene-editing tool built specifically for filamentous fungi, achieving editing efficiency approaching 90%.
By using fPE7max to activate a master regulatory gene called laeA, the team awakened silent biosynthetic pathways across multiple fungal species, yielding eight molecules entirely new to science.
Three of those molecules showed early anti-cancer properties in laboratory tests, including one with selective toxicity against human breast, hepatic, and leukaemia cancer cells, opening a potential new pipeline for drug discovery.
Fungi's Forgotten Chemical Library
Fungi have a remarkable track record in medicine. Penicillin, the antibiotic that transformed twentieth-century healthcare, came from Penicillium mould. Statins, the cholesterol-lowering drugs taken by hundreds of millions of people, have fungal origins too. Yet despite this history, the vast majority of fungal chemistry remains unexplored.
Part of the reason is circumstantial. When grown under sterile laboratory conditions, fungi suppress the very gene pathways that produce potentially useful compounds. In the wild, these pathways are activated in response to competing bacteria and environmental pressures; in a petri dish, they go quiet. The result is what researchers call "silent gene clusters": stretches of DNA that encode complex molecules but produce nothing unless deliberately switched on.
Xue "Sherry" Gao, Presidential Penn Compact Associate Professor in the Department of Chemical and Biomolecular Engineering and the Department of Bioengineering at the University of Pennsylvania, has spent years trying to change that. Her lab's latest work, published in Nature Biotechnology, describes a new gene-editing platform designed specifically for filamentous fungi, the thread-like moulds that include Aspergillus and Penicillium.
Building a Better Editor for Filamentous Fungi
The dominant gene-editing technology of the past decade, CRISPR-Cas9, works by cutting both strands of a DNA double helix simultaneously. In filamentous fungi, this blunt approach tends to produce unintended mutations, making precise edits difficult. A newer technique called prime editing sidesteps this problem by rewriting DNA sequences without breaking both strands, but adapting it for fungi presented its own challenges.
Two obstacles stood out. First, prime editing relies on a guide RNA, a molecular instruction set that tells the tool where to go and what to write. When the edits required are large, these instructions become long and fragile, degrading before the job is done. Gao's team solved this by incorporating a stabilising protein called fLa, which acts as a protective binder, shielding the RNA from degradation.
Second, fungal cells have their own repair mechanisms that detect newly introduced genetic changes and revert them. To prevent this, the team integrated a specialised protein that temporarily suppresses the fungus's natural repair response, long enough for the new genetic
code to become permanent.
The resulting tool, fPE7max, achieved editing efficiency approaching 90% in tests across several fungal species.
What the Editing Revealed
To demonstrate what fPE7max could do, the team targeted laeA, a master regulatory gene that controls a broad network of biosynthetic pathways in filamentous fungi. By precisely editing out the molecular sequences that keep laeA's translation repressed, the researchers successfully activated silent gene clusters, prompting the fungi to produce compounds they would otherwise never make in a laboratory setting.
From this, first author and postdoctoral researcher Chunxiao Sun and colleagues isolated 18 structurally complex molecules. Eight had chemical structures entirely new to science. Of those eight, three showed promising anti-cancer properties in early laboratory tests. One molecule in particular exhibited selective toxicity against human breast, hepatic, and leukaemia cancer cells, according to the research team.
Limitations and the Road Ahead
These findings remain at an early, pre-clinical stage. Laboratory tests on cell lines are a long distance from human clinical trials, and the anti-cancer activity observed has not yet been tested in animal models or humans. The researchers themselves describe this work as a "proof-of-concept," and the molecules identified are described as "lead compounds," meaning starting points for further development rather than candidate drugs.
The team plans to deploy fPE7max across a wider range of fungal species, moving away from opportunistic searches for useful compounds toward what Gao describes as systematic optimisation. The research was supported by the National Institutes of Health under grant R35GM138207 and by startup funds from the University of Pennsylvania. How quickly this platform might yield clinically relevant candidates remains an open question.
Fungi's broader potential as a source of novel therapeutic molecules is attracting growing scientific attention, and fungal genetic engineering is rapidly expanding the tools available to researchers hunting for the next generation of medicines.