Could A Fungal Pandemic Be “The Last of Us?", with Arturo Casadevall
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people might be familiar with what was a video game and then became a TV show called The Last of Us. And I wonder if you could explain the premise of this show and why it's connected to some of your work. Let's start by saying that I never watched the show except for the opening trailer. You haven't seen the world, so you don't know. Samara West. Samara West.

They're working on a cure. And I began to get emails from people saying, hey, were you one of the advisors to this show? And I said, what are you talking about?

That's Arturo Casadevall, professor of microbiology and immunology at the Johns Hopkins Bloomberg School of Public Health. And he's the author of the new book, What If Fungi Win? The premise of the show is that a scientist in 1968 predicts that with global warming, cordyceps could adapt to higher temperatures and thus become a human pathogen. Fungus.

Yes, that's the usual response. Fungi seem harmless enough. Many species know otherwise. And that's what the show is based on. And how is it connected to my work? Well, I've been working on why are the fungi pathogenic for a very long time. While the TV show is just science fiction, scientists like Casa de Val, who study fungi, are already preparing for what they say might be inevitable.

Can we be dealing in the future with a fungal pandemic? And the answer to that is yes. Most of us just think of fungi as a delicious pizza topping or an annoying, itchy infection. Yet we don't usually think of fungi as something deadly. To me, that was a very interesting question because the plants, the fungi are the major pathogens of plants. So plants are terrified of the fungi, if they could think.

The insects are terrified of the fungi. The frogs are terrified of the fungi. So the question is, what makes us different? What makes humans different is that our internal body temperature provides natural immunity against fungi. But just like in the TV show, climate change is changing everything. Currently, there are no reasons for fungi to evolve to be able to withstand higher temperatures. But what if that were to change? What if, for instance, the world were to get slightly warmer?

Well, now there is reason to evolve. The world is getting harder. All life on this planet is going to have to adapt. Period. So here is the big concern. The big concern is the fungi are adapted.

And if they adapt to higher temperatures, they will defeat our temperature barrier. If fungi keep adapting to higher temperatures on Earth, a fungal pandemic like The Last of Us wouldn't just be science fiction. You will need to have a fungal disease that is communicable, right? You need to be able to infect, go from person to person, or you need to have some event

in the environment that showers humanity with spores somehow. So that is a possibility. There is nothing biologically to stop a fungus from making spores in the lung, such that when you cough it out, the spores will come out. But there is a glimmer of good news in what might seem catastrophic. We do have the foresight to prepare and possibly prevent a fungal pandemic. We need to heighten

awareness of this because we can do something about it. Vaccines can be made. New drugs can be made.

and we can be more aware of the threats so that we don't get blindsided with a fungal pandemic. Welcome to Big Brains, the podcast where we translate the biggest ideas and complex discoveries into brain food you can use. I'm your host, Paul Rand. On today's episode, the science of how fungi are adapting and why we need to prepare for a fungal epidemic.

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Most people, of course, are probably giving thought to this thinking they know what fungi means or fungi. And that's something that they eat or see in the woods on a walk. But I wonder if you can talk about the kinds of fungi that you are talking about and what a basic explanation of what they are. So, Paul, that's a great question. Most people don't think about fungi except in the supermarket or in the woods after it rains when they see mushrooms.

But the majority of fungi are unicellular, microscopic. Those are the ones that cause disease. And my understanding from your book is there are about 6 million species of fungi, which is far more than probably most people ever thought possible. At least. That's an estimate. Most of the world has not been mapped. And very little work has been done to know what fungi are in your backyard.

But people don't seem to fear the fungi. The fungi may harass them. They may give them a nail infection. They give them athlete's foot. But people don't walk around saying, you know, I'm really worried I'm going to die of a fungal disease. Normally, and I guess maybe before we get into the idea of challenges, the bad parts of fungi, there are some really good parts of it.

Well, last night I had a glass of wine. You can't have a glass of wine without fungi. Basically, fermentation. They are foodstuffs. They make a lot of our medicines. How many of listeners may be taking statins? Well, they're made by a fungus. Penicillin is made by a fungus. Many of the other antibiotics are made by fungi. But most important for the planet, what the fungi do is that they are the big degraders.

So when a tree falls down in the forest and rots, it is the fungi that return all those nutrients back into life.

So they are essential for life on earth because we know it. We might not know just how many fungal species are out there, but we do know a lot about the ones we've already come into contact with. And Casa de Val had personal experience with one fungal disease in the 1980s during the height of the AIDS epidemic. What really changed my life was going into Bellevue Hospital in New York City in the mid-1980s.

And what I saw there was a devastation that is hard to describe. The hospital was full of young people dying of a disease that we had never heard before. The idea that something can happen in medicine that was not known was shocking. And what was killing them was not so much the virus that we know now as HIV, but opportunistic infections.

And these are infections like fungi was one of the big problems causing pneumocystis. We didn't think in the mid-1980s that you could ever make drugs to control this virus. So the idea was if we're going to help these people, we got to work on what's killing them, the fungi. And therefore, that's why I went into working on the fungi.

The study of fungal disease has always been a backwater in the sciences. Viruses and bacteria have always sucked up all the energy in the room for one simple reason. Most fungi are not pathogenic because you are protected by your temperature. You're hot. Fungi can't survive above 97 degrees, coincidentally, the average temperature of humans. So fortunately for us, we've had a natural immunity. And we don't think about it, but our temperature, when we walk around every day,

is enough to keep out most of the fungal world.

So we're getting a huge amount of protection. Basically, they can't replicate at our temperatures. They basically, once they go into us, they shut down and the immune system cleans them up. And that's why most people don't worry about dying of fungal diseases. That is until 2009 when everything changed. A fungus known as Candida auris started doing something scientists thought wasn't possible. So here is something. This fungus was unknown to medicine.

to 2009. And then a couple of years later, it begins to show up in patients in three different continents. And the isolates are not related. You can't say, well, some of the happen in Venezuela, happen in South Africa, happen in the Indian subcontinent. You can't say, well, you know, somebody brought her on a plane and infected. No, these things are not related. They're in fact quite different. And now we have a major problem with Candida auris, which is

rapidly disseminating and causing problems throughout the United States. Turned out is something you've been hearing a lot about lately. A fungus known as Candida auris, the CDC is on alert, citing a rapid spread, particularly in health care facilities. Candida auris is a form of yeast. For a healthy person, it's usually not harmful, but for those with weakened immune systems, it can be deadly.

More than half of the states have now reported cases of the drug-resistant fungus. So the first reports all happened in people who were very immunosuppressed.

So the fungus almost found a way to adapt. Once it gets into a hospital, it's very tenacious and it's very hard to clean. So if you look, the CDC put out a paper a couple of years ago just showing that this thing was spreading state after state. And right now it's primarily a problem for immunocompromised patients. But we have 7 million immunocompromised patients in this country. A lot of people potentially at risk. So the question I pose is,

to you and to our readers is what's going on here. Fungus not known to medicine shows up simultaneously in three continents and they are not related. They appear to be independent eruptions. And I give you something. What is the one common denominator? It isn't soils. It isn't culture. It isn't food. It's all three places are experiencing global warming. So we have proposed that this is the canary in the coal mine.

It is the first example of a fungus that was living in the environment, not bothering any humans, with the capacity to cause disease. But then it adapted. And even though we can treat it, I don't want to scare any listeners off, and even though the likelihood of anybody getting it is very small, the bottom line is the fact that it happens should be a big warning signal. So here is the big concern. The big concern is the fungi are adapted.

And if they adapt to higher temperatures, they will defeat our temperature barrier. Because if you have a fungus that can grow, let's say, let's use the Fahrenheit scale, above 95 degrees, well, it's not pathogenic today. But if in two or three years it can go to 98 degrees, well, we're not going to keep them out. Speaking of life adapting, and this was news to me, but I didn't realize that our body temperatures are actually getting a bit cooler. That is an incredible result.

It was a very interesting paper. What they did is they collected temperature readings for decades, going back, you know, over 100 years now. And they showed that the average human temperature is dropping. So in other words, your great grandparents were warmer than you are.

So how can that be? After all, you know, we are the same species. Well, it turns out that 100 years ago, people were infected with a lot of things that they're not infected in our clean world today. They had worms. Many of them had tuberculosis. Even if it was latent, it will raise your temperature possibly. And anyway, they lived in a different world where there was more inflammation.

And inflammation is why when you get an injury, it feels warm. So in a more inflammatory world, they had higher temperatures. Our world is cleaner. But this leads to a problem because if the fungi are adapting or we're getting colder, we're going to meet earlier than we think. So we have two things going on. We have adaptation. But if adaptation is not enough, then the temperature is also making them change. And it's going to change them in very unexpected ways.

But one of the other things is that climate change is not only making some of these fungi stronger, it's actually helping them proliferate. So where we are today and where we are tomorrow, just on a volume basis, could actually be quite different. There's been studies, including one from Duke University recently that was going on with mice that really brought this to life. Can you talk us a little bit about that study and what it helps show us?

So what that study showed us is that we don't have to worry only about adaptation. The situation gets worse because when you take this fungi and you put them in a warmer environment, well, they have these mobile DNA elements that then begin to reassort their DNA. So when they reassort their DNA,

Some of them come out drug-resistant, and some of them can acquire more virulence. If the fungi continue to adapt to our new climate, becoming resistant not only to our natural temperature barrier, but also resistant to antifungal drugs, what will that mean for us? Well, Casa de Val and other scientists hope to develop better antifungal drugs, and even possibly a one-size-fits-all antifungal vaccine. That is after the break.

Thank you.

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Today, we only have a number of antifungal drugs that are effective at killing fungi diseases. But the reason why we don't have more of these drugs might actually surprise you. When you look at the tree of life, animals, us, cows, monkeys, are closest to the fungi rather than to the plants, rather than to the amoeba and things like that. The little ones, the microscopic, and the big ones, the mushrooms, are really the same type of organisms.

And what makes them really interesting is that they are your closest relative. So we share a lot of the biochemistry with them. And that actually becomes a problem when you try to make antifungal drugs. Essentially, it becomes harder to make a drug that can fight your relatives and not you. The fact that we are biochemically so similar to the fungi, what it means is that it is difficult to find a difference. And if it's difficult to find a difference...

The difference is the target. You want to kill the fungus and not kill the person. There are also some implications of certainly some serious side effects of some of the least of some of the current antifungal medications. Well, our best antifungal was made on the year that I was born.

It's known as amphotericin B. If you want to know my age, 1957 I was born. And the drug was known for many years as amphoterable. Okay. Now, over the years, physicians have figured out how to make it less toxic.

But it tells you something that the most effective drug that we have for some fungal diseases, we now have others, is a drug that was developed a long time ago with a lot of toxicity. Not only do we not have many antifungal drugs in the event of a pandemic, but there's another growing problem. Antifungal resistance is on the rise.

meaning fungi are becoming so strong that they can actually defeat the drugs that are designed to kill them. That's right. Resistance, like everything else, continues to be an increasing problem. Although some of the current fungal diseases are so resistant that it's just very hard to treat. But it's not just people who are facing antifungal resistance. Scientists are also seeing the same problem in the wild with animals and agriculture. The fungi are responsible for

for losing an enormous amount of the volume of our crops. Every major crop has a major fungal pathogen. Officials in Colombia confirm a fungus destroyed banana plantations in Asia and Australia, and it has now reached South America. So the wheat have a fungal pathogen, the rice have a fungal pathogen, you name it. Agriculture fights a constant battle with the fungi just to make sure that we have our food at the table.

This is obviously an area that is of tremendous importance to society. I mean, maintaining the food supply. And it doesn't make the news, but the fungi are destroying entire ecosystems today. In our lifetimes, we have seen an amphibian catastrophe. A single fungus has spread throughout the world and has killed untold numbers of frogs and driven many to extinction. In North America, we've seen a problem with the bats.

The bats were well until 2006, and then a fungus got into this country somehow. The bats are like you. They are 37 degrees in the summer. They are resistant to this fungus. But in the winter, there are no insects. They need to hibernate.

So their temperature drops and this fungus kills them. Millions of bats are being killed. For nearly two decades, bats across North America have been decimated by a deadly disease called white-nose syndrome. Patches of pale white fuzz caused by a fungus appear on infected bats. There was an amazing paper recently in Science associating the declines in bats with increases in baby infant deaths.

And the way this happens is a single individual by tracking data sets was able to show that as the bats go down, the pests go up and people use more pest control and the pest control gets into everywhere and there's an association. So it just shows you all this is connected. So when I tell you that there are catastrophes going on in the frog ecosystems, in the bat ecosystems, they will affect us.

If we were to look out a few years here and check back with you in five years, what kind of progress do you think you and some of your colleagues will be making? One of the things that we want to do, and we were working on this, and this was put on hold by the COVID pandemic, is to try to construct a threat chart.

In other words, you got six million species out there, right? Which ones do you think we should worry about most? Well, I would say something that is close to your temperature, something that can cause disease in another animal or a plant, because the fact that it can cause disease in an insect means that it can defeat an insect in the insect.

So I'd be looking for things like that. So I would worry more about something that can grow up to 35 to something that can only grow up to 30 degrees. You're at 37. So the closer you are, it can grow to your temperature, the more I worry about it. And so that to construct that, because I think that if we had that, we may begin to look at where our future threats are. And that could become very important for preparedness.

Doctors often don't think of fungal disease because it is rare. But what's interesting about the fungi is the fungi don't kill you rapidly. So when they tend to cause disease, it tends to be chronic, like chronic sinusitis. So fungal diseases are not reportable, the majority of them. They're not reportable. Why? Because they're not usually communicable.

So, there's a colleague of mine, David Denny, but he's led a remarkable effort to try to document how many people are dying of fungal disease in any one country. And every few years, he publishes a paper in the media journal. And I think the numbers are in the millions that are dying from fungal disease. I looked at it relatively recently. So, we're not talking about something that causes only a few cases. When you put the human population together,

We're talking about an untold amount of human death and suffering. But the one thing is, when you look at the numbers, the problem of fungal diseases gets worse every year. Is this a likelihood that we will not have a medication to treat it once symptoms arrive, but actually could be a vaccine that could prevent that infection from even coming? There is so much criticism of what happened with COVID. It's important to remember that within one year, within one year,

We had vaccines, we had drugs, and we had monoclonal antibodies. But vaccines is a completely different strategy. And here is the problem, Paul. Who would you vaccinate? You want to vaccinate the people at risk. The people at risk are often immunosuppressed. But guess what? Because they're immunosuppressed, they may not make a good response to the vaccine. So it becomes much harder to make a vaccine. Can you make it? Yes. We have vaccines for the immunosuppressed.

But again, you think about it from the pharmaceutical company point of view. You're making a vaccine for a niche population that is going to be harder to test and harder to respond. There will have to be a major societal effort to basically get this done. There are people today working very hard to make vaccines for bats.

For example, my colleague Bruce Klein and his colleagues at the University of Wisconsin. People are working on these problems. But what people need to know is the efforts are minuscule compared to what's going on for other more pressing diseases. And this is normal human nature. The fungi get worse every year, but incrementally. COVID hits us and turns our society upside down.

At this point, you're probably thinking to yourself, "Okay, I need to fear all fungi and even worry about the prospect of a fungal pandemic." But there is another side to fungi that has a lot of promising potential. Surprisingly, they could just as easily usher in a new area of development. And it turns out they may be the key to revolutionizing our modern industrial world.

So what we haven't talked about is all this stuff that's going on in trying to develop the fungi as new materials. Like, for example, I invite your listeners to Google fungal leather. So it turns out that certain fungi, you can grow them in the shape of a handbag.

and you can grow things and then you compress the mycelium. And this stuff is actually biodegradable. It doesn't come from animals. We're working with NASA in using some of the properties of fungi for shielding. The biggest problem out in space is radiation. Are you going to be shipping lead up there? It turns out that they make melanin, and this melanin is a very powerful shielding material.

Fungal construction materials. Some people are using compressing the fungus into some sort of bricks. And you know what? Our civilization depends on materials. If you think about Stone Age, Bronx Age, Iron Age, Silicon Age. Well, imagine an age, the biological age.

And I believe that the fungal world has a lot of new stuff that it's going to give us. It's also, whether it's air conditioning, construction materials, fungi is present in all of these different areas that are impacting our lives. Let's just talk about air conditioning.

It turns out that when you buy mushrooms, they're cooler. The reason that they're cooler is because they have a lot of water and as soon as the water evaporates, the fungi are cooler. This is the same phenomenon why you feel cold when you step out of the shower, even though your bathroom is full of steam.

water, even a little water evaporating makes you feel cooler. So one of the things, and it was one of those really fun things that you do in the world of science that doesn't have, we made a prototype air conditioner in which we went and bought some of these mushrooms.

From the supermarket, we put in a fan that came from a computer cooling fan, drove air through, and it dropped the temperature almost 10 degrees centigrade. That's a big drop. As long as those mushrooms had water, the air going out of them

was cooler. Now, eventually they will dry up. But what I would say is you could scoop them and cook them at that point. To those who cook, the best example of how much water mushrooms have is you go to the supermarket and you buy all these big mushrooms and then you cook them and they become little tiny things. And you say, what happened to this? Well, the water went out.

So it does examples and there are all the people thinking about water, uh, fungi as filtration systems. You can put them in areas in which the water is flowing and they will absorb out of the water many of these things that we have wanting it out. So there is a lot of people experimenting. I think there is going to be a lot more fungi in our world, in our future. Big Brains is a production of the University of Chicago Podcast Network.

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