By: Justine Brooks
3 Nov, 2022
Fungi — microorganisms such as yeasts, moulds and the more familiar mushrooms — are incredibly diverse. They could be as miniscule as a single-celled organism, or as massive as three blue whales. In fact, the largest organism on Earth is a fungus. Some of these microbes are harmless and some produce life-saving medicines, yet others exploit the host and cause serious diseases.
“Part of the challenge is that fungi are actually very closely related to humans,” says Leah Cowen, co-director of CIFAR’s Fungal Kingdom program. “Often, many drugs that we use to kill the fungus have very serious side effects for the host. The spread of multidrug-resistant fungal pathogens poses a big threat to the efficacy of our very limited arsenal of antifungals.”
In a Q&A with CIFAR, Cowen talks about the threat of fungal disease, her work to improve treatments, and the core questions facing the future of the field.
CIFAR: Could you tell us about your most recent projects?
Leah Cowen: My research program focuses on understanding what allows some microbes to exploit the host and cause disease. We also develop new strategies to thwart drug resistance and treat life-threatening infections, specifically by uncovering vulnerabilities in fungal pathogens at genome scale. We started by working on a fungal pathogen called Candida albicans, which is one of the most prevalent fungi in the context of human disease. This particular organism has two copies of every gene, similar to what we have as humans. We delete one copy using a specialized approach and replace the other copy with a system that we can turn off. That way, we can turn off expression of each gene in the genome to study its function.
We also screen very large libraries with tens of thousands of molecules. We’re interested in finding molecules that do cool things – kill the pathogen or have interesting bioactivity. We’ve identified lots of exciting molecules and targets for antifungal discovery. We often need to have a focused effort to optimize our lead molecules, so that they can differentiate and selectively inhibit the fungal protein and not affect the host.
CIFAR: What are the benefits and risks of fungi?
Leah Cowen: My work focuses on deadly pathogens, but fungi have many benefits to humanity: they are critical for decomposing dead matter and recycling nutrients, and they can turn crop waste into biofuels and eat plastic. There are at least 350 species of fungi that we consume as food — we use them to make bread, alcoholic beverages, and cheese — and a number of them are hallucinogenic. They also produce life-saving vaccines, medicines, and antibiotics.
Of course, there are many threats too. Fungi can infect about a billion people every year and kill about 1.5 million people per year. That outpaces the mortality rates for malaria or breast cancer, and is on par with tuberculosis and HIV, so a huge death toll that’s largely underappreciated. Fungi also cause a major threat to food security and biodiversity. They’re the only organisms that are causing extinctions in real time (for example, they’ve killed off ~90 species of frogs).
CIFAR: What are the potential fungal threats of the future? How does climate change play a role?
Leah Cowen: Only rare fungal species can survive and replicate at mammalian temperatures, which is why there are relatively few fungal diseases in mammals. This is one reason why humans and mammals maintain warm body temperatures — to fight off infections. There’s been concern with an organism called Candida auris. Nobody had heard about it until 2009 when it was isolated from a human ear. It had never been identified in any clinical repositories until the discovery of multiple different evolutionary distinct isolates of the pathogen separated by thousands of years. To achieve that level of diversity, it had to have been evolving in the environment and it’s thought that elevated temperatures allowed it to adapt to better infect and thrive in the human body. As the Earth warms, we’re expecting that more organisms will adapt and there will be more and more that can survive at human body temperature.
CIFAR: How do we treat fungal diseases currently, and how can we improve human health in the future?
Leah Cowen: We have approximately three major classes of antifungal drugs compared to several dozen classes of antibacterials. One of those classes targets the fungal cell wall while the other two target some aspects of the fungal cell membrane. Some of these antifungals are quite toxic, and some are not very good at killing fungi, so they can arrest fungal growth but leave a viable population that can accumulate mutations and evolve drug resistance. One strategy is combination therapies. We actually launched a startup company called Bright Angel Therapeutics, which is working on two major programs to develop molecules that cripple drug resistance mechanisms to be deployed in combination with antifungal drugs.
CIFAR: What have you seen in your field that once seemed impossible but is now real?
Leah Cowen: It was a struggle not long ago to engineer mutants for a single gene in a human fungal pathogen, really limiting the kind of functional discovery you could embark on. Now, we engineer thousands of mutants and we integrate barcodes which allow us to execute experiments in a pooled format. We can do highly multiplexed complex assays that look at thousands of different mutants in multiple conditions. This has transformed the kinds of questions we can ask and the way in which we can look at biology without a lens only focused on what we already know.
CIFAR: What are some opportunities for collaborations with other CIFAR programs?
Leah Cowen: We haven’t yet engaged with the CIFAR AI community, but would love to; I think that may be the next frontier. We’ve had fantastic collaborations with our colleagues in the Humans & the Microbiome program. The synergy there is pretty obvious but perhaps less obvious is our collaborations with colleagues in the Earth 4D program where we’re looking at fungi in extreme environments. Those have both been very fruitful collaborations with multiple catalyst grant programs actively underway.
CIFAR: What do you hope to accomplish in your work in the next 10 years? Where do you see your field going in that time?
Leah Cowen: There are many questions I would like to answer. One would be, how do fungi sense their environment and go from living in balance within their human hosts, to causing disease? Another is how do fungi adapt, including to a changing climate, and what are the implications for the emergence and spread of infectious disease? Also, how can we predict and prevent the evolution of drug resistance? I think it is critical to think about drug resistance and strategies to discover and develop new treatments; given how much resources are required to develop a new drug, we want to make sure we’re developing ones that last.
I expect that interdisciplinary science will continue to transform research on the fungal kingdom. Certainly from my own experience, our most exciting discoveries have come from collaborations across disciplines. What drives my passion for the CIFAR program is that we bring together such diverse and incredibly creative and innovative people from different disciplines who work collaboratively to tackle these grand challenges.
We hosted a workshop in November 2021, with CIFAR and the Burroughs Wellcome Fund, to chart the future challenges and opportunities posed by the fungal kingdom. The discussion was timely given the fungal threats and opportunities that were exacerbated by the COVID-19 pandemic. To understand the scale of these issues, it is important to think about how we report and track fungi that cause disease in humans, plants, and animals. Public education and outreach are also essential because there is much to be gained by enhancing awareness of strategies to mitigate the threats posed by fungi and to harness their extraordinary potential.
As part of CIFAR’s 40th anniversary celebration, “Believe the Impossible: The Future of…” highlights researchers whose big ideas could transform their field over the next 40 years.
CIFAR is a registered charitable organization supported by the governments of Canada, Alberta and Quebec, as well as foundations, individuals, corporations and Canadian and international partner organizations.