Could The Last of Us Really Happen?

Rebecca Casale | Articles | About | Subscribe | Published October 2023

The Last of Us sees a parasitic fungus called Cordyceps devastate humanity, turning people into violent zombies. Based on the existence of real body-snatching fungi in arthropods, could this fate ever really befall humans?

Could The Last of Us Really Happen? | Science Me

What is Cordyceps?

BBC Earth, Naughty Dog, and now HBO share their own special symbiotic relationship. It revolves around a group of bizarre and devastating organisms called Cordyceps; the evolution of which is the inciting incident in The Last of Us.

Cordyceps belong to the fungi kingdom, which means they're genetically closer to animals than plants in the universal tree of life.

If we zoom in on the fungi kingdom, we meet five separate fungi phyla: club fungi, sac fungi, tree fungi, zygote fungi, and pot fungi. And if we zoom in again on sac fungi, we meet familiar friends such as budding yeasts, penicillin, and Cordyceps.

Types of Fungi: Phylum Basidiomycota, Ascomycota, Glomeromycota, Zygomycota, and Chytridiomycota

Fungi make some weird lifestyle choices. Since they're not autotrophs like plants, they can't make their own energy from sunlight. Instead, they draw their energy from other organisms, making them heterotrophs like us.

Not having a mouth, your average fungus takes in energy by absorbing nutrients from its environment. Different species are either parasitic meaning they eat living things, saprophytic meaning they eat dead things, or symbiotic meaning they live in/on living things as part of a mutually beneficial trade of services.

Cordyceps fungi are cold-hearted parasites, controlling the brains and feeding off the bodies of all manner of arthropods including cicadas, butterflies, beetles, wasps, and ants.

In 1859, while travelling in Indonesia, the naturalist Alfred Russel Wallace had the dubious honour of discovering the Cordyceps species Ophiocordyceps unilateralis, which feasts on the bodies and brains of carpenter ants.

When an ant becomes infected with Cordyceps, he compulsively leaves the nest and seeks out a cooler, moister environment that's optimal for fungal growth. Under the influence of the fungi, he then bites into the major vein on the underside of a leaf and remains fixed there until he dies.

Having created a zombie ant and consumed his tissues and internal organs, the fungus is ready to reproduce. A fruiting limb emerges from the corpse and a puff of spores released into the air. The spores are dispersed by the wind to land in the vicinity of other ants and the monstrous lifecycle can continue.

A zombie ant infected with a Cordyceps fungus.

For the creators of The Last of Us, there are two wildly inspiring things happening here. First, a brainless fungus takes over the brain of another organism. And second, the fruiting body that grows out of its head looks super creepy.

Could Cordyceps Infect Humans?

The Last of Us came out as a game all the way back in 2013. Not being a gamer, it only entered my world in 2023 when it was adapted into a TV series. I was basically so far behind the curve that I was ahead of the next curve. That's right, the curve is a circle in my mind, you linear mutha.

The story in the TV show opens on John Hannah as Dr Neuman, an epidemiologist who coolly introduces us to the nature of Cordyceps.

"There's a fungus that infects insects. Gets inside an ant, for example, travels through its circulatory system to the ant's brain, and then floods it with hallucinogens, thus bending the ant's mind to its will." - Dr Neuman, TLOU

Cool. It's definitely more complicated than flooding the brain with hallucinogens but this is a handy narrative to explain how a brainless fungal microorganism could overtake an animal's survival drive.

"The fungus starts to direct the ant's behaviour, telling it where to go, what to do, like a puppeteer with a marionette. And it gets worse. The fungus needs food to live, so it begins to devour its host from within, replacing the ant's flesh with its own." - Dr Neuman, TLOU

Most parasites don't actually want to kill their hosts because it destroys their own habitat. In this case, however, the lifecycle of the fungus is so short compared to the ant that it's content to kill its host, die with it, and let the next generation flourish elsewhere. Next comes Dr Neuman's dire proclamation:

"Fungi cannot survive if their host's internal temperature is over 94 degrees. And 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." - Dr Neuman, TLOU

He's saying humans are too hot for Cordyceps. And he'd be right. One of the benefits of having such a high body temperature is to keep fungal growth at bay. This certainly isn't the only barrier for Cordyceps to parasitise humans, as we'll see in a moment. But his whole argument basically hinges on this idea.

"One gene mutates and an Ascomycete, Candida, Ergot, Cordyceps, Aspergillus, any one of them could become capable of burrowing into our brains and taking control not of millions of us, but billions of us." - Dr Neuman, TLOU

Pump the brakes. A SINGLE gene mutation! You know that's not how this is going down John Hannah. We'll unpack some genetic elements in a moment.

"Billions of puppets with poisoned minds permanently fixed on one unifying goal: to spread the infection to every last human alive by any means necessary." - Dr Neuman, TLOU

Yeah, maybe. But maybe not. Remember when it took many months of virality before COVID infections reached the millions? This included recovery and reinfection. However, in TLOU, Cordyceps is often fatal because the infected kill themselves before they develop symptoms, die of their wounds, starve, or are mercilessly hacked to pieces by Joel Fucking Miller. This all bodes better for survivors and not so well for the parasites that are running out of hosts.

Infection Stage	Symptoms
	Runners are fast, irritable, violent zombies with hyphae sprouting out of their rotting bodies.
	Stalkers lurk, croak, and sometimes end up growing into the wall as they transform.
	Clickers have blooming fungal brains which turn them into terrifying, twitchy echolocators.
	Shamblers are slow and solitary with swollen, flingable bulbs containing corrosive ichor.
	Bloaters are large, powerful, and overgrown with heavy duty fungal armour.
	The Rat King is a twisted fusion of clicker, stalker, and bloater body parts.

"And there are no treatments for this. No preventatives, no cures. They don't exist. It's not even possible to make them." - Dr Neuman, TLOU

He's right, there are no treatments for diseases that don't exist yet. There are, however, three classes of antifungals in clinical use which may tackle a novel fungus. Azoles are drugs that inhibit the formation of the fungal cell membrane, echinocandins deplete the fungal cell wall, and polyenes cause fungal cells to leak ions and small organic molecules leading to cell death.

As we saw with COVID, we could also count on big pharma to invest heavily in a fast-tracked cure. Despite the fact that fungal diseases kill 1.5 million people each year, the burden is not geographically even, making this a question of finances over feasibility. Throw more money at the problem and we can probably solve it.

Why We're Truly Safe From Cordyceps

The best argument against a Cordyceps pandemic is that parasitic fungi are highly host-specific. In evolutionary terms, while they likely started out as plant pathogens, Cordyceps began to manipulate animal hosts from around 48 million years ago after lengthy periods of co-evolution.

There are 750+ species of Cordyceps, each specializing in a single host species. Their interactions only emerged through prolonged evolutionary periods of molecular trial-and-error.

One doesn't simply generalise a mind-controlling parasitic lifestyle to an entirely new animal phylum with a single gene mutation. There are many physiological and molecular mechanisms involved. For instance:

Cordyceps produce bioactive compounds which target brain function. Multiple biological products imply multiple genes, or at least gene splicing alternatives, pointing to multiple gene mutations.
Cordyceps may interfere with the production or reception of neurotransmitters to alter host behaviour. This modulation of neurochemistry must also be evolved over time.
Cordyceps fungi may also alter the ongoing gene expression of host cells, allowing them to suppress the host immune system and promote their own parasitic growth. It's another password to unlock.

Luckily for us, the last common ancestor of humans and insects lived 500 million years ago. We've really gone our separate ways since then, demonstrated by such facts as bees have stingers in their asses and we don't.

This vast genetic gap makes it a lot harder for Cordyceps to cross the species barrier from arthropods to humans.

So, ruling out some spectacular AI-powered genetic engineering, it's extremely improbable that we'll ever see Cordyceps or any other known fungi adapt to manipulate human brains so dramatically. It simply takes a long, long time for natural selection to unlock these molecular passwords.

Fungal Threats to Humans

Now, don't relax! There are still fungi that want to kill you and have been evolving to do so for a while.

The world is teeming with millions of species of fungi, around 600 of which are associated with humans. Those that infect us are bad for our health, but there are species with live within us quite symbiotically.

You body is well colonised, I'm sure, with complex populations of fungi which make up your mycobiome. This forms part of your larger microbiome which includes bacteria, fungi, viruses, and their runaway genes.

As far as the immune system goes, it's a fine balancing act to tolerate commensal fungi but defend against full-on invasion.

Most of the action occurs on your skin and in your lungs. When you step into nature, you inhale thousands of fungal spores which are potential threats to your wellbeing. Likewise, when you share towels or high five your gym buddy, fungi transfer between you. Most of the time, there's no problem because you're warm-blooded and have a working immune system.

When fungi do successfully invade the body, it's usually through the skin, hair, nails, mucous membranes, or lungs. This is mycosis.

Athlete's foot, jock itch, and ringworm are all caused by the overgrowth of moulds called dermatophytes which normally live on the skin, hair, and nails. The resulting skin infections aren't quite on a level with clickers, but they are pretty gross.

Aspergillus is another common mould that affects the respiratory system. While you probably breathe it in every day and don't get sick, it can lead to life-threatening lung infections in transplant recipients and other immunocompromised people. Symptoms include chest pain and coughing up blood, but zero zombification.

Some examples of human-associated fungi and where they attack the body.

Climate change is certainly a risk factor for a rise in fungal infections. However, rather than an exotic fungus like Cordyceps jumping into humans, we're infinitely more likely to suffer at the spores of those that can already infect humans, or at most their close relatives. In fact, this may have already begun.

In 2009, a novel fungus called Candida auris emerged rapidly across multiple continents, suggesting a possible link to environmental changes. The fungus is from the Candida family which usually causes yeast infections, but this emerging pathogen has several aggressive features.

The novel Candida auris thrives at human body temperature, spreads person-to-person, is multi-drug resistant, and causes severe infections once in the bloodstream.

For healthy people, Candida auris is probably not a cause for worry. But for immunocompromised people, it can kill due to the lack of treatment options. Why? You guessed it. They make up only a fragment of the population so there's no financial incentive for big pharma to make antifungal treatments.

In 2022, the WHO released a fungal priority pathogens list in the first global effort to systematically identify threats. There are 19 fungal pathogens on the list, of which four are considered critical concern:

Fungal Pathogen	Description
Cryptococcus neoformans	An opportunistic yeast that's inhaled from the soil to affect the lungs, and later the central nervous system and blood. High mortality. Some resistance to antifungals.
Candida auris	An invasive yeast that attacks the blood, heart, central nervous system, eyes, bones, and internal organs. High mortality. High resistance to antifungals.
Aspergillus fumigatus	An invasive mould that's inhaled from the environment to cause disease in the lungs and brain. High mortality. Some resistance to antifungals.
Candida albicans	A symbiotic yeast of the microbiome that can grow out of control to cause infections in the mucous membranes. High mortality. Low resistance to antifungals.

Final Thoughts

The Last of Us builds a captivating world and I'm all up in it, so long as it remains fiction. Fortunately, the reality of Cordyceps fungi is far more nuanced, the specialised adaptations to arthropods having taken millions of years to evolve.

If there were an attempt to capture humans, there's no way we're looking at a single gene mutation. That would be like dropping a typewriter down the staircase of the Empire State Building and expecting Romeo and Juliet at the bottom.

It would take much longer than our lifetimes for the symbiotic relationship to develop. Indeed, the timeframe required would see both parasite and host evolve many times over into altogether new species.

Rebecca Casale is a science writer and illustrator in New Zealand. If you like her content, share it with your friends. If you don't like it, why not punish your enemies by sharing it with them?