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Some mice have crummy immune systems.
Like, especially the ones we rely on to learn about our own health.
When they’re bred in sterile environments and cut off from the real world,
how is that supposed to teach us anything
about real humans in the real world?
But some researchers argue that wild mice can bridge that gap.
A wild mouse’s immune system has way more in common
with our own than those of lab mice do.
And I’m about to tell you why it could be a
huge game changer in modern medicine.
[INTRO]
More research is conducted in lab mice than any other animal.
And that’s because scientists know what they’re getting into
when they study lab mice, from their genetic makeup
to what in the environment is likely to throw them off.
But over years of mice being optimized for answering research questions
rather than for maintaining their own health,
the poor little guys have become really inbred.
To keep their genomes totally uniform,
researchers may breed the same animals
with their siblings for 27 generations at a time.
And researchers like it that way, because it means they’re
less likely to accidentally attribute an
experimental outcome to the wrong source.
For example, if you feel funny after eating a peanut butter sandwich,
it could have been because you developed a nut allergy,
or it could have been the sushi you ate earlier in the day.
Or it could have been the medication you took with the sandwich,
or any number of factors that you might not be able to
narrow down because you’re exposed to so many new things every day.
But the lab mouse eats the same thing for every meal of every day in the
same room and hasn’t been exposed to peanut allergens or bad sushi.
So if a lab mouse is looking a little low after getting
an immunotherapy drug, it was probably because of the drug.
And that’s why research is still conducted in animals.
Mice have organs and blood and hormones that serve bigger roles
in the living animal than a scientist could observe in a section of tissue.
By looking at a tumor cell culture under the microscope,
you could learn a lot about its uncontrolled reproduction.
But you wouldn’t be able to see how it travels
to other parts of the body and spreads cancer.
So whole lab mice help scientists develop therapies for whole people.
But researchers are learning that in one area,
these lab mice don't really resemble humans.
It’s their immune systems.
Despite all of the lab mouse research to find cures
for human immune disorders, wild mice have more
human-like immune responses.
It’s the very qualities that make lab mice so appealing for research
that also make them less relevant to solving our problems.
Remember, researchers are using
inbred populations of pretty much genetically identical mice.
And their immune systems haven’t been introduced to
as much stuff as ours because they live in a sterile lab environment.
So when researchers have tried to take treatments that worked in
lab mice and give them to humans, they’ve failed over and over again.
One paper published in the journal Nature claims that about
75% of drugs fail somewhere between mouse trials and human trials.
Then the first attempt at clinical testing in humans
loses another 70% from there, and so on.
And researchers believe one reason for that drop off
is that lab mice aren’t representative of us.
It’s not the only reason drugs fail in humans,
but we might be taking that step from rodents to us a little too early.
To bridge that gap, some researchers started
studying animals that resemble us more closely.
We can still use all of the incredible discoveries that have been made
over years of lab mouse research by comparing them to a wild relative.
Now, compared to inbred, sterile lab mice,
pretty much every mouse is wild.
So when researchers describe wild mice in their experiments,
they run the gamut from pet shop mice to the
little guys roaming around your local field.
Those wild mice differ from more commonly studied lab mice
because there’s genetic variation between individuals.
And that might not sound surprising, but when you consider
that inbred lab mice don’t have that, it’s a huge factor.
Beyond that, wild mice use their genes differently than lab mice.
Every gene in your genome isn’t going full tilt at all times.
It’s similar to when you’re driving.
Just because you can floor the gas pedal
doesn’t mean you’re doing 90 in a school zone.
You accelerate more when you need to.
For your immune system, the time you need
to kick it into full gear is when you’re under attack.
So in a study published in 2016, scientists exposed a group of lab mice
to a few herpesviruses and yellow fever virus.
The kind of stuff that a wild mouse might encounter in their daily travels.
But those lab mice grew up in sterile environments,
and so did their parents and their parents’ parents.
So before this infection, their immune systems were totally untrained.
Virus? Who’s she?
So these lab mice produced fewer immune cells
activated fewer immune cells, and had more
inexperienced immune systems than wild mice.
Across the board, their immune systems were less primed for action.
And once the viruses invaded their systems, everything changed.
The lab mice adapted. They started showing off some genes
that they had previously hidden away.
Their genes and immune responses started looking more, like wild mice.
Hardened wild mice have been exposed to more
dangerous viruses throughout their lives.
And all that dangerous stuff can awaken certain hidden
and slumbering sections of their genes so that
they can help the mouse fight off the threat.
So being exposed to viruses and parasites
changes how mice use their genes.
And if researchers only study sterile inbred lab mice that
don’t use some of their immune-related genes,
they’re more likely to overlook those genes even
in a study specifically aimed to understand the immune system.
This 2016 study gives hope that there are ways
to counteract those effects! And lab mice don’t even need
to be directly infected to make those changes happen.
In the same publication, the researchers
gave a new set of lab mice wild roommates.
Every parent’s sleep-away camp nightmare.
But the wild roommates had a really positive impact
on their less experienced buddies.
They exposed the lab mice to stuff they wouldn’t have
otherwise been exposed to, and ramped up their genes
to be more prepared and more closely resemble the wild mice,
and by extension, us.
So there are ways to make lab mouse experiments more relevant
to those of us who don’t live in completely sterile environments,
which is pretty much all of us.
But because there’s still so much value in lab mouse experiments,
some researchers are studying a new type of mouse.
One that’s not quite a lab mouse and not quite a wild mouse.
They’re breeding lab mice with wild mice
in an initiative called the Collaborative Cross.
The Collaborative Cross is a new,
more diverse group of mouse breeds.
Basically, researchers still get to work with
a select group of mice that have well understood genes,
similar to lab mice.
But now they have more kinds of mice and they’re more diverse,
like the mice you’d find in the wild.
Using this approach, researchers can get reproducible results
and include more representative genetic variation.
And it’s already led to more human-like results.
For example, you have a gene called Foxp3
that keeps your immune system from fighting itself.
But not everyone has the same amount of Foxp3 in their genome.
And researchers think that may be at least part of why
some of our immune systems turn against themselves
in autoimmune disorders, while that doesn’t happen for other people.
But we wouldn’t know all of that without a study published in 2017 that
found more variable amounts of Foxp3 in Collaborative Cross mice
than inbred mice, making them one step closer to us.
And that’s just the first stepping stone across the gap to humans.
The next stepping stone is called Diversity Outbred mice.
Instead of orchestrating a new set of Collaborative Cross breeds,
Diversity Outbred animals are the babies of any and all mice coming
from the Collaborative Cross founding mice.
So now there’s a way more representative sample.
And, just as researchers hoped, those mice have helped them
narrow down a gene related to tumor suppression in pancreatic cancer.
They combed through the genomes of 270 Diversity Outbred mice
and found that this gene consistently popped up even across
the really broad group of mice.
And that gives researchers added confidence that it’s not just a fluke
that might come from the unnaturally restricted sample of inbred lab mice.
So we’re heading into a more representative future
with more narrowed down causes for immune disorders
and immune-mediated diseases, including new cancer targets!
Ultimately, studying wild mice in the lab doesn’t mean
that the existing inbred mice are a broken model system.
It just helps us sift through those findings
and focus on the stuff that’s more likely to treat disease in the real world.
Lab mice are pretty fundamental to research.
But after those smarty-pants scientists gather tons of immunology info
from their mice, they need to do something with it.
That’s where the next fundamental research skill comes in: data analysis.
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[OUTRO]