With the fungus Cryptococcus neoformans as a model, Casadevall sees virulence (disease severity) as a framework in which damage can come from the host, microbe or both.
This idea frees you, he says, from approaches that have created “a microbiological archipelago” with specialties that barely interact with each other.
Casadevall, like Darwin, is looking for patterns.
In 1899, fungal diseases were rare; by 1999, they had become “distressingly common.” Why?
“We changed the host,” he said. Medical progress made us more vulnerable to fungi. And then came “the cataclysm of AIDS.”
A common fungus usually harmless to healthy people, C. neoformans can cause serious illness in immune-compromised people such as those with HIV/AIDS.
“C. neoformans is one of the leading causes of death in Africa, eclipsing tuberculosis, and yet you don’t hear about it,” Casadevall said.
Fungi, with over 1.5 million species, are major pathogens of plants, reptiles, invertebrates and amphibians and are now devastating ecosystems of bats (which are mammals) and frogs.
Still, there are very few fungi harmful to mammals with intact immunity. Could the answer be in the distant past?
Casadevall investigates Cryptococcus neoformans, a common fungus that is harmless to healthy people but can cause serious disease in immune-compromised people.
Photos: Bill Branson
The age of mammals begins after the K-T event, a mass extinction of three-quarters of plant and animal species on Earth—including all non-avian dinosaurs.
Most scientists believe that K-T was triggered by a massive comet/asteroid impact. Fires, smoke and dust obscured the sun and photosynthesis was arrested for over 6 months.
Yet the mass extinction gave mammals a chance to produce new forms, such as whales and primates.
“But if reptiles were so fit, why did they not reclaim the Earth?” Casadevall said. The larger ones were likely killed by the impact of the blast, the disruption of food sources, the chilling of the planet and fungal diseases. However, some reptiles survived. Given the advantages of reptiles over mammals on energy consumption, one wonders why the cataclysm was not followed by a recovery of reptiles and a second reptilian era.
Imagine a primeval forested planet where all trees have fallen, creating a massive compost layer for fungi to feast on.
The animals that made it were largely warm-blooded. Although dinosaurs were warm-blooded, they could not have regulated their temperatures the way we do.
This is key: Most fungal species do not threaten mammals because fungi do not tolerate the mammalian core temperature range. We are too warm for them.
Thus fungal selection acted as a filter for the emergence of mammals, he argued.
“I have no proof, no experiment. It’s all thought...I have no idea if it’s accepted and I frankly don’t care. I never have to apply for funding for this and this is fun, this is why I went into science.
“We should be able to write and debate things,” he said, “and this is something you don’t see too much any more.”
Meanwhile, his work on Cryptococcus neoformans is backed up by 20 years of research and publication. Collaborating with physicists, chemists and geneticists, Casadevall developed new insights.
A fungus that lives in the soil, C. neoformans probably developed its virulence through interactions with amoebae over the last billion years. Using both microscopic and quantum models, he found that the C. neoformans capsule appears to be a dendrimer, a repetitively branched molecule that is “incredibly unusual. This raises huge basic science questions…that are very biologically relevant.” This work is ongoing.
Turning to melanins, pigments found in all animal kingdoms, Casadevall reviewed their protective function as “nonspecific armor.”
He found that melanin in fungi shows that they use radiation for food.
“We thought we had a major discovery,” he said, but two “single-word journals” rejected it.
Nonetheless, the news sections of those same journals, and many others, covered these findings.
“We should be able to write and debate things,” Casadevall said, “and this is something you don’t see too much any more.”
Tracing his paper’s progress, Casadevall addressed the state of scientific publication today. His follow-up study showed that “misconduct accounts for the majority of retracted scientific publications” and that “males are responsible for a lot of this.”
This got a laugh from the audience, but Casadevall cautioned that “all we show is that the females are missing,” raising the possibility that males and females carry out misconduct at the same frequency, but that females don’t get caught.
With his fungi and radiation study now confirmed by another journal, Casadevall insists that fungi do have a limited ability to photosynthesize (convert energy from the sun and other sources of radiation), turning blue-green and black in the process.
And the in vivo application? Ingestion of melanin in black mushrooms (an edible fungus) can protect mice against lethal irradiation.
“We hope to go into clinical trials. It has tremendous potential usefulness in radiation therapy.”
Meanwhile, as the climate warms, many non-pathogenic fungi may adapt to higher temperatures enough “to take down immunologically intact humans.”
He does not have a predictive model and can find “no chaotic signatures” in his own model for virulence. (Chaos means that small differences translate into big changes.) Nonetheless he keeps asking fundamental questions.
“Think about it,” he said. “We don’t know why we can make vaccines very easily for some organisms and not others. Wouldn’t you want to know if the system you’re working with is chaotic or not? Yet something so fundamental has never been asked. Are our immune responses chaotic?”
And the answers to his existential questions from a fungal point of view?
- Why are we here? K-T event and fungal selection.
- Why are we so hot? To keep the fungi away.
- Why do we eat so much? To maintain high temperature.
- Why are mammals the dominant large animals? Fungal selection kept down the reptiles. No second age of reptiles!
“Mammals make no sense without the fungi,” he says. “Mammals were going nowhere until the K-T event.”
If you bring infected frogs into a 37-degree room (normal human temperature at Celsius) it will completely eradicate the fungus. Perhaps, he said, global warming will save the frogs by roasting the fungus.
“And I leave you with that image,” he concluded. “That perhaps somebody will benefit from all that pollution.”
The talk is archived at http://videocast.nih.gov/summary.asp?Live=13248