Furthering research on fungi will require more model organisms. Although most fungi are difficult if not impossible to culture in the laboratory, their DNA can be separated from their symbionts and identified using metagenomics, and editing their genes with CRISPR should make them culturable. Their interaction with other organisms can be elucidated with new imaging advances.

Even in some well-characterised species, between 20 and 30 per cent of genes and gene clusters are either unknown or only hypothetically associated with human disease, and need to be better characterised. Pangenome approaches will illuminate biochemical pathways, including those that underpin disease associations such as the (currently controversial) link between Aspergillus sydowii and lung cancer.³

Fungal biobanks and seed-bank-like repositories could help decode the relationship between genotype and phenotype in the same way that biobanks of genes have helped research.⁴ Building and maintaining culture collections are also important tasks if we are to retain archival knowledge of diverse fungal species, many of which are dying in the mass extinction — and to understand what spurs fungal evolution and extinction.

One way to study commensal fungi is to separate fungal from host genes using “shotgun” metagenomics,⁵ a sequencing technique that allows researchers to study the genomes of entire microbial communities without needing to culture them first. This has already made it possible to advance the study of the human skin mycobiome⁶, the fungal component of the microbiota.

However, the interactions themselves also need to be studied, which requires an understanding of community ecology: how organisms interact within specific habitats. New insights are making it possible to study commensal strains in animals in vivo — in the gut mycobiome of lab mice,⁷ for example. Beyond standard lab-mouse work, novel model systems like hydra are also being developed to study fungal interactions within microbial communities.

Such approaches will be required to understand important changes we are making to commensal relationships: fungi, for example, play a crucial role in promoting carbon capture and in agriculture. This may be changing, however, as a consequence of synthetic phosphate use in soil.⁸ The synthetic phosphates change plants’ long-established symbiotic relationships with fungi, which may have knock-on effects for farming and for climate change.

The same fungus can exist as either a commensal or a pathogenic organism. For example, Candida albicans is an opportunistic fungus that can choose either lifestyle. As a benign resident of the human microbiome, C. albicans is an ovoid yeast. However, as it transitions to a pathogen, its shape changes, extruding filamentous hypha that penetrate host cells. Research is under way to study the gene products relevant in pathogenesis. The damage done by C. albicans, for example, is largely attributable to a peptide it secretes, candidalysin. It has been shown to be essential in the ability of C. albicans to cause cell damage and host immune activation.

Environmental factors encourage these transitions. Climate change has forced fungi into new niches as higher temperatures push them to adapt to the sorts of conditions that have, for millions of years, kept them from colonising warm mammalian bodies. Additionally, agricultural use of the same few types of fungicides used in medicine to fight infections have ensured that fungi adapt to our available drugs, which are now losing efficacy,⁹ and global trade has brought non-native species into places that have not evolved defences against them.

Scientific advances will change the way we study other mechanisms of pathogenesis and how they arise, take effect and spread. They will also allow us to identify specific agricultural practices, trade routes and climate problems that can be targeted for biosecurity interventions.

Mitigation strategies include vaccines and RNA interference (via extracellular vesicles as a promising route),¹² new small-molecule drugs and natural compounds that are isolated from bacteria and other sources where anti-fungal strategies have evolved. There is a need to replace broad-spectrum agricultural fungicides that poison the entire kingdom, moving towards a more tailored approach involving targeted fungicides that leave soil-fungal communities intact, lock down carbon and do not cause resistance in clinical anti-fungals. Research into these tailored approaches is ongoing but not yet mature.

More positively, two novel small-molecule anti-fungals — olorofim and fosmanogepix — are now in phase III trials.¹³ New synthetic chemicals are also being developed, as well as new approaches for delivering them. Manipulating the fungal microbiome or virome may guide their behaviour into being more favourable for us.