Surviving the drug: how fungi grow under stress

We would like to congratulate Professor Judith Berman on her election to the U.S. National Academy of Sciences and to the American Academy of Arts and Sciences, two of the most prestigious scholarly societies in the United States, in recognition of her life-long scientific accomplishments, including transformative contributions to our understanding of how pathogenic fungi respond to antifungal drugs.

Fungal infections of the bloodstream and other deep tissues kill 15% to 40% of patients who develop them, even when those patients are treated with antifungal drugs that, in laboratory tests, should work against the infecting strain. For decades, this gap between what the lab predicts and what happens in patients was attributed mostly to host factors, immune status, and difficulties in drug delivery. Berman’s work over the past decade has reframed the question: a substantial part of the answer lies in the fungus itself, in a phenomenon she defined as antifungal tolerance.

In a 2018 Nature Communications paper, Berman and her team showed that drug tolerance and drug resistance, terms long used interchangeably in the fungal literature, are in fact two different things. Resistance is a genetic property of the entire fungal population: cells carry mutations that allow them to grow even at high drug concentrations, and standard clinical assays measuring the minimum inhibitory concentration after 24 hours are designed to detect it. Tolerance is something else entirely. In a tolerant isolate, only a subpopulation of cells, ranging from 5% to 90% of the population, manages to grow slowly at drug concentrations well above the inhibitory threshold. This slow growth becomes visible only after 48 hours, which is precisely why standard clinical tests miss it.

Berman’s group developed quantitative tools that make tolerance visible and measurable. Using these tools, they showed that tolerance is a reproducible feature of each fungal isolate, that it depends on the cell’s general stress response machinery rather than on direct interactions with the drug target, and that it can be eliminated by combining the antifungal with a second compound that disables those stress responses. Most importantly, in patients with bloodstream Candida infections, they found that isolates causing persistent infections, those that fail to clear despite repeated antifungal therapy, showed significantly higher tolerance than isolates that were rapidly eliminated by the same drugs. From there, she further developed a conceptual framework distinguishing between different fungal drug responses that now guides research in the field.

Berman built much of her scientific foundation at the University of Minnesota. She began her career working on telomeres, the protective caps at the ends of chromosomes, and on chromatin, the packaging of DNA that controls which genes can be read by the cell. She then moved to Candida albicans, a fungus responsible for many human infections, studying how it switches between its rounded yeast form and its long, branching hyphal form. Her 2006 Science paper showed that C. albicans can become resistant to antifungal drugs by carrying an abnormal number of copies of certain chromosomes, a phenomenon known as aneuploidy. Her 2013 Nature paper overturned a long-held assumption about the species: while C. albicans was thought to always carry two copies of its genome in each cell, she demonstrated that it can also exist with a single copy, opening up new possibilities for genetic research on this important pathogen. She moved to Tel Aviv University in 2011 and closed her Minnesota lab in 2015, continuing her research at the Shmunis School of Biomedicine and Cancer Research.

The National Academy of Sciences, founded by Abraham Lincoln in 1863, is the highest scientific honorary society in the United States and advises the federal government on matters of science and technology. Election is by current members, and Berman joins as a primary affiliate of the Section of Microbial Biology and a secondary affiliate of the Section of Genetics. The American Academy of Arts and Sciences, founded in 1780 by John Adams and other revolutionary-era leaders, recognizes excellence across the sciences, humanities, and arts, and counts more than 250 Nobel and Pulitzer laureates among its members.