Over 125 million years ago, a new trait showed up in some ancient mammals – a
trait that was invisible to the naked eye and that seemed beneficial at the time.
This trait was a new chemical marker that appeared on the surface of all of the animal’s cells,
a sugar molecule known as ‘alpha-gal’.
Alpha-gal is still found on mammal cells today. And, yes, in keeping with its
powerful, boss-sounding nickname, it’s got a really important job.
It’s one of an array of molecules that cells use to signal to the immune system
that they’re part of the body, so the body doesn't start basically attacking itself.
And we know this molecule has been around for a very long time, because it’s found
all over the mammal family tree, from kangaroos, to aardvarks, to whales.
But there is one - and only one - group of mammals that doesn’t have it:
the catarrhine primates, which are the monkeys of Africa and Asia, the apes, and us.
Around 20 to 30 million years ago, our ancestors stopped producing alpha-gal.
And not only have we lost it,
but we actively produce antibodies against this molecule - which no other mammals do.
So what’s going on here? Why did our lineage ditch an otherwise-universal
feature of mammal biology and start producing antibodies that target it?
Well, this unique trait of ours might be the molecular legacy of an ancient
catastrophe: an outbreak of a devastating, deadly pathogen.
We can tell that the catarrhine primates, including us, lost alpha-gal sometime after
we split from our common ancestor with the monkeys of the Americas
around 40 million years ago – because those other primates still produce it.
And the ancient gene that makes it is still in our genomes today,
lying dormant on our 9th chromosome, having been inactivated by mutations.
So we have a pretty good understanding of when and how we lost the ability to make
this molecule. But why this happened is a much more complicated question.
After all, it’s not like it left any hard evidence in the fossil record.
And we’ve never seen it happen naturally in any other mammal. As far as we can tell,
in the entire evolutionary history of mammals, it’s only happened to our group.
So, we’ve had to turn to evolutionary theory and our understanding of the
immune system to try to tease out this story.
My first question is: what could turn the loss of alpha-gal into an advantage?
Because, I mean, presumably this chemical was really useful to a lot of other mammals for a long time.
So why would losing it end up being helpful enough that our
ancestors ended up passing along the inactivated gene to their descendants?
This has led to a fascinating, but pretty dark, hypothesis.
We know that pathogens - especially really deadly ones - have been a major driving
force in our evolution, thanks to the selective pressure they put on the populations they infect.
And we know that our immune system is constantly being shaped by the pathogens
it encounters - both over the course of an individual’s life and over evolutionary time.
That’s kind of the whole point of it.
So here’s what might have happened: Around 20-30 million years ago, a deadly pathogen
that had alpha-gal on its surface might’ve found its way into some ancient primates.
And since both the host and the pathogen had the same molecule on their cells,
the immune systems of those primates couldn't make antibodies against the
pathogen … without also targeting their own cells.
But, in this scenario, a small number of individuals just happened to have mutations
that inactivated their alpha-gal gene, so their cells didn’t have that molecule on them.
Now, random mutations happen all the time – they create the natural
genetic variation that we see in every population.
Sometimes they’re harmful and are weeded out of the gene pool by natural selection.
Sometimes they’re neutral. And sometimes they confer a survival advantage.
And this might’ve been one of those advantageous times.
Because the mutants that didn’t have alpha-gal could then make
antibodies that targeted the pathogen without mistakenly locking onto their own cells, too.
This would’ve allowed their immune systems to fight the pathogen,
which potentially helped them survive and pass those genetic mutations along.
Another possible scenario is that the pathogen used the host’s alpha-gal as a kind of
‘docking’ site to attach to and infect the host’s cells. In this case, too,
primates losing that molecule would have had better protection.
Either way, the pathogen was so deadly, and the mutations so advantageous,
that the inactivated alpha-gal gene became ‘fixed’ in our lineage…
Meaning: the working version of the gene disappeared entirely
from our gene pool as those that had it died out.
So, today, all catarrhine primates descend from those mutant survivors of that horrible outbreak.
And we still carry their inactivated alpha-gal genes,
as well as their ability to produce antibodies against it.
In fact, antibodies that bind to alpha-gal are
among the most abundant types of antibodies that we produce.
Which is one of the main reasons that we can’t easily receive organ transplants
from other mammals. Their cells and tissues are covered in alpha-gal,
which our antibodies bind to and our immune system rejects.
Now, while this whole story works in theory, it’s really hard to conclusively prove or disprove.
Like so many things about the deep past, the story of alpha-gal is a working hypothesis.
But! We do have some observations that support it.
For one thing, we know that a lot of pathogens have alpha-gal on them,
including some viruses, bacteria, fungi, and protozoa.
So it’s totally possible that some unusually dangerous version of one
of these emerged and plagued our ancestors.
And we know that, around 20 to 30 million years ago, the monkeys of
the Americas and the lemurs of Madagascar were geographically isolated from the catarrhines.
This may explain why those other primates still have alpha-gal on their cells.
Because, if the outbreak was restricted to Eurasia and Africa,
then they wouldn’t have been exposed to the pathogen – so they weren’t subjected
to the selective pressure that drove the loss of that molecule in our lineage.
We can also look to modern experiments to try to fill in the missing pieces of this puzzle.
For example, researchers deactivated the alpha-gal gene in pigs in the lab,
and they found that those pigs almost immediately started producing antibodies against the molecule.
This is a lot like what’s thought to have happened in the ancestors of catarrhines
20 to 30 million years ago.
Those with the mutant, deactivated version of the gene were innately
able to produce antibodies against alpha-gal.
And the advantage of that change in protecting against pathogens?
We can test that in the lab, too.
Researchers have knocked out the alpha-gal gene in lab mice. Then they infected them
with pathogens that have that molecule, and then measured how well the mice could resist them.
And those mice turned out to be better able to resist infection by protozoa and bacteria.
But, they also found that this came at a cost.
Those mice stopped being able to reproduce earlier in their lifespan than normal mice.
This seems like a classic evolutionary trade-off. And it’s entirely possible that the loss of
alpha-gal led to the same trade-off in our primate ancestors as it does to mice in the lab.
Those primates would have had better protection against pathogens with alpha-gal.
But on the other hand, they might’ve had fewer offspring.
Now, as for whether this still affects us, we don’t actually know.
I mean, a lot of evolution has taken place between
now and then, so we might be compensating for our shortened reproductive lifespans,
if we do indeed have them in other ways.
And this tradeoff may partly explain why the total loss of alpha-gal has been so rare in mammals.
It takes a really nasty pathogen, and one that uses a particular molecule,
for such a loss to be beneficial.
That situation seems to have only taken place in catarrhine primates,
leaving us with this odd biological quirk 20 to 30 million years later.
Now, this is just a hypothesis, though a plausible one,
and there are many aspects of why we lost alpha-gal that we may never understand.
The details of this story, like so many others in natural history,
might simply be lost to deep time.
But it only further proves that – for literally billions of years – our
ancestors have had to contend with all sorts of deadly pathogens.
And the evolutionary pressures they put on us have shaped our genes,
our cells, and our bodies in ways that make us who we are today.
Now as bad as this pathogen sounds, there’ve been others - check out our episode,
“The Pandemic That Lasted 15 Million Years.”
We want to thank Dr. Jessica Brinkworth of the
University of Illinois Urbana-Champaign for reviewing the script for this episode.
And we’ve gotta thank this month’s alpha Eontologists!
Annie & Eric Higgins, Chase Archambault, Colton,
Jake Hart, John Davison Ng, Melanie Lam Carnevale, and Alex Tamai
Become an Eonite at patreon.com/eons and you can get fun perks, like submitting a joke to make me read
in front of the camera, like this one from Foster and Mark F.
They both submitted the same joke.
Have you ever tried to eat a clock? It's very time consuming.
That seems off brand.
[laughs]
Ok you can connect the dots on that one.
And as always thanks for joining me in the Adam Lowe studio.
Subscribe at youtube.com/eons for more journeys in deep time!
[singing] In a minute, I'ma need a sentimental Man or woman to pump me up
It’s the song of the summer.