Could The Last of Us Really Happen?

Rebecca Casale | Articles | About | Subscribe | Updated July 2024

In The Last of Us, a very real parasitic fungus from the arthropod kingdom makes the jump to human hosts, turning us all into raging zombies. Could anything like this ever really happen?

Could The Last of Us Really Happen? | Science Me

What is Cordyceps?

There's a special symbiotic relationship between BBC Earth, Naughty Dog, and HBO that revolves around a group of bizarre and devastating organisms called Cordyceps. Like all mushrooms, yeasts, and moulds, Cordyceps belong to the fungi kingdom, making them genetically closer to animals than plants:

Besides being our evolutionary cousins, fungi also share our animalistic eating habits. In the broadest sense, plants are autotrophs, meaning they make their own energy (from the Sun). Yet fungi are heterotrophs, just like us. They steal their energy from other organisms simply by gobbling them up.

The fungi kingdom is split into five phyla called club fungi, sac fungi, tree fungi, zygote fungi, and pot fungi. Zoom in on those handsome sac fungi and you'll meet budding yeasts, penicillin, and Cordyceps.

Types of Fungi: An Illustrated Phylogenic Tree

Fungi make some weird lifestyle choices. Depending on the species, they're either:

Parasitic = They eat you while you're alive
Saprophytic = They only eat you while you're dead
Symbiotic = They eat you alive but are nice about it

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

How Cordyceps Attacks Arthropods

While travelling in Indonesia in 1859, 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 a Cordyceps fungus, he is doomed. The fungus takes up residence in the ant's brain and controls its movements. Before long, the ant compulsively leaves the nest and seeks out a cooler, moister environment that's optimal for fungal growth. He then bites into the major vein on the underside of a leaf and remains fixed there until he dies.

Having consumed the ants tissues and organs, the fungus is ready to reproduce. A fruiting limb grows out of the corpse until, finally, it releases a puff of spores into the air. The spores are dispersed by the wind and land in the vicinity of other ants so the monstrous lifecycle can begin again.

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 parasite somehow takes over the brain of another, supposedly more complex, organism. And second, the fruiting body that grows out of the ant's head looks super creepy.

How Cordyceps Attacks Humans

In The Last of Us game, Cordyceps is spread by breathing in spores in the air, or by being bitten by an infected person. Inside the body, the fungal cells multiply and spread, invading the brain and central nervous system to take control of the host's mind. As the fungal infection spreads, it causes dramatic physical changes. The host is consumed and eventually loses all traces of their former self.

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.

Could Cordyceps Really Infect Humans?

The TV show opens on John Hannah as an epidemiologist named Dr Neuman who coolly introduces us to the devastating nature of Cordyceps. Here are some of his claims and the scientific reality today.

Claim: "There's a fungus that infects insects... floods it with hallucinogens, thus bending the ant's mind to its will."

Reality: True enough. Cordyceps secretes neuroactive compounds, including neurotoxins and possibly hallucinogens, to overtake a the ant's survival drive and have it die in the optimal place for spore dispersal.

Claim: "The fungus starts to... devour its host from within, replacing the ant's flesh with its own."

Reality: True. Most parasites don't want to kill their hosts because it destroys their habitat and reduces their changes of transmitting to a new host. In this case, however, the Cordyceps lifecycle involves killing the host to complete its reproductive phase. This strategy is viable because the fungus can infect multiple hosts in a relatively short period.

Claim: "Fungi cannot survive if their host's internal temperature is over 94 degrees."

Reality: True enough. Most fungi are mesophilic, thriving at temperatures between 20°C to 35°C (68°F to 95°F). Pathogenic fungi in humans thrive at human body temperature (37°C or 98.6°F). The upper thermal limit for many fungi is 40°C (104°F), beyond which their cellular processes become impaired. One of the benefits of being warm-blooded is to keep fungal growth at bay.

Claim: "Currently, there are no reasons for fungi to evolve to be able to withstand higher temperatures. But what if... the world were to get slightly warmer?"

Reality: True. Like all organisms, fungi can undergo evolutionary changes in response to selective pressures. If an environment heats up, fungi with mutations that allow them to survive and reproduce at higher temperatures may be naturally selected.

Claim: "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."

Reality: Pump the brakes! To manipulate a human brain, the fungus has to make sophisticated interactions with the nervous system, well beyond the scope of a single gene mutation. The jump from insects to mammals alone demands multiple new genes and biological pathways, including host recognition and adhesion, immune evasion, toxin production, and nutrient acquisition. They need long evolutionary timescales to emerge. This is very silly.

Claim: "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."

Reality: Wildly speculative. In TLOU, Cordyceps is often fatal because infected people suicide before they turn, die of their wounds, starve to death, or are mercilessly hacked to pieces by Joel Fucking Miller. In the spore-free TV version, where infection only spreads through bodily fluids, I'd put money on humans breaking the chain of transmission rather than billions of infected zombies.

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

Reality: False. There are multiple classes of antifungal drugs available today, including azoles (eg, fluconazole), echinocandins (eg, caspofungin), and polyenes (eg, amphotericin B). These drugs interfere with cell membrane synthesis and cell wall integrity to kill many types of fungi. In high-risk populations (immunocompromised people like organ transplant recipients and chemotherapy patients), antifungal drugs are used prophylactically to prevent infection.

The Evolution of 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 gain-of-function 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 quite some time. The world is teeming with millions of species of fungi, around 600 of which are associated with humans. Those naughty pathogenic varieties are certainly bad for our health—but it's nice to know there are also many species that live inside us symbiotically.

You body is well colonised 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. Every time 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 cause deadly lung infections in 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.

After COVID, 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:

	*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, with the specialised adaptations to arthropods having taken millions of years to evolve.

If there were an attempt to capture humans, it would require more than 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.

The reality is, it would take longer than your lifetime for Cordyceps to evolve to infect humans. Indeed, it would be a timeframe so great that both parasite and host could evolve many times over into altogether new species.

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