Sinking our teeth into Cordyceps

I get pretty easily hooked by a good television series, and for me, HBO's 'The Last of Us' was no different. But what was special about this series was that always lurking - or at times straight up lunging - behind the plot was a microbe.

Me last week, discovering my new favourite TV show

So today on Microbial Mondays, be aware: this is far more fantasy and thought experiment, rather than cut and dry science. And, there will be spoilers.

As I hope you know if you've read this far (or at least are comfortable in knowing because it is kind of a spoiler), the storyline of 'The Last of Us' takes place in a world in which Cordyceps, which is indeed a real fungus in our own universe (and you can eat it! To the left you can see the dried Cordyceps that I've been chomping on while watching 'The Last of Us'), has evolved to infect humans. And when those humans are infected, they turn into aggressive zombies whose only remaining purpose in the half-life they live is to bite, and therefore infect, more humans - all with the aim of creating new hosts for the fungus that they carry.

So far, there has not been a greatly detailed focus on how exactly this fungus evolved... Which perhaps is because not everyone finds fungal evolution terribly interesting. But I am willing to take the risk that you, dear reader, are as curious about microbial evolution as I am.

What we know so far, as of episode 8, is that just before the pandemic in the universe of 'The Last of Us' broke out, this Cordyceps species supposedly evolved to withstand warm temperatures in a flour factory in Jakarta, Indonesia. That same flour factory was where the first human cases were seen. One employee bit several of her coworkers after becoming infected, and several other employees went missing.

As for the "zombification", this is explained using a similar principle as the perhaps now-infamous real-world zombie fungus that changes the behaviour of the ants that it infects to stimulate its own transmission. In brief, we are told over the course of the plot unfolding, that the apocalypse-introducing Cordyceps fungus of 'The Last of Us' decays yet also preserves the bodies of the infected. This balance between decay and hijacking allows the fungus to make use of those who were once humans as vessels. Namely, vessels for moving the fungus around and transmitting it to new human hosts. The fungus also makes its human vessels highly aggressive, presumably because a bite is the best way for the fungus to spread to a new person.

So, we have a model for an even worse, fungal pandemic. But how likely is it?

Let's make a bite-sized (hehe) investigation into it, and let's start at the beginning.

Jakarta. And flour.

Well, either the humans still alive in the world of 'The Last of Us' are missing something big, or the story of the first infections is far more fantastical and unrealistic than you might first conclude. Of course, we know from the ant zombie fungus, Ophiocordyceps unilateralis that it is possible for fungi to exert a sort of mind control over other organisms. However, to put it very simply, humans are a heck of a lot more complicated than ants. Plus, as far as we know, there are no species of the very diverse group of fungi known collectively as Cordyceps that come anywhere close to being able to play puppet master for any organism more complicated than an insect. The likelihood of a fungus so suddenly jumping to a new and complex host like humans is low, and then the likelihood of it being able to immediately and drastically change that human host's behaviour is even lower.

The ant zombie fungus probably co-evolved - i.e. evolved side by side - with ants for tens of thousands or millions of years to be able to so intricately mess with the minds of those insects. Plus, as far as I have read, it arguably still doesn't exert such detailed control over ants' behavior as the fictional Cordyceps in 'The Last of Us' does over human behaviour. The zombie ant fungus basically just gets infected ants to climb upward, and quite quickly die on a high branch from which fungal spores can rain down on ants passing beneath. It does induce biting - but only a single, final bite into a leaf, so that the ant's mandibles can anchor its body to whatever high branch it climbed onto.

In reality, it would take many long years for a fungus to evolve to be able to exert such precise puppet master-esque control over humans. And, it surely would need some in-between steps. For instance, hypothetically, the ant zombie fungus Ophiocordyceps unilateralis could first jump to infecting, say, rats, and then over millenia it might co-evolve with those rats to adapt to controlling a more complex mammalian nervous system. Then, maybe one day a human would get bitten by a rat, and over another few thousand years the fungus would evolve to be able to puppeteer its human victims.

But this would all be far more chancy and complicated than it sounds. Over generations and generations, the fungus would have to slowly, slowly evolve to become masterful in carefully preserving and triggering aggression in human victims. As Merel Sijbranda covered in the third article of her Mycobacterium tuberculosis miniseries on Microbial Mondays, evolution relies on diversity. Over time, some individual fungal strains, each of which would have small unique features compared to other strains in the same species, might by chance evolve to keep their human victims alive for slightly longer than other strains. Then, those particular strains that don't kill their victims so quickly might be able to reproduce more, because the humans that were infected with those particular strains could walk around more - and thereby come into contact with more humans to infect. If that were to happen, then over time, the majority of humans infected with the fungus would be infected with these strains that are compatible with a long life. If you can call it a life, that is.

Likewise, the fungus would also have to slowly, slowly evolve to gain whatever genes and proteins are involved in triggering aggression in its human hosts. Maybe, for instance, one strain of the fungus would at one point in time accidentally mess with its human host's amygdala, an area of the brain involved in controlling defensive behaviours. Let's assume that as a result, its human host would then act as though it were under attack at all times... Leading to the biting behaviour seen in 'The Last of Us. If that fungal strain was also readily transmitted through bodily fluids like saliva, that new biting behaviour of the host could give this new aggression-triggering, amygdala-invading strain an advantage. Namely, it would be able to transmit to more uninfected victims than its more 'peaceful' sister strains. Over years and years, this particularly 'aggressive' strain of fungus might become the dominant one in the human population - just as Omicron has become the dominant type of SARS-CoV-2 in our reality.

Of course, this is all very hypothetical and just a fun thought experiment, but the point I am trying to make here, is that evolution takes time. And, a lot of it.

In other words, there's just no way that a fungus could independently, and so rapidly, make the massive evolutionary leap straight from growing on flour to zombifying humans. To satisfy my scientists' brain, I just decided that in the world of 'The Last of Us', there must have been infected zombie mammals living in that flour factory in Jakarta, who had been co-evolving with Cordyceps for thousands of years unbeknownst to the owners, and who bit that first human.

Have you also been watching 'The Last of Us'? Are there any somewhat scientific topics from the show that you'd like Microbial Mondays to dig in to? Let me know in the comments!