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As a SciShow viewer, you can  keep building your STEM skills with a 30 day free trial and 20% off an annual premium subscription  at Brilliant.org/SciShow. 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.

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