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  • We do a lot of health research in mice.

  • They're small and easy to take care of,

  • and more suitable for experiments than actual human people.

  • But mice aren't people.

  • We're sorry you had to find out this way.

  • And neither are rats, guinea pigs, rabbits,

  • or other animals used to study stuff that happens with humans.

  • Although mice are pretty much our favorite model organism for medical research,

  • they are… a model.

  • They're not exactly like humans,

  • and they don't always respond to drugs the same way we do.

  • Researchers can design mouse models that are really close to certain human diseases,

  • and use that to make incredible progress in medical research.

  • But sometimes they get tripped up.

  • Here are six times the science only worked in rodents --

  • for better or for worse.

  • First, take Alzheimer's disease.

  • In the brain of an Alzheimer's patient, a protein known as beta-amyloid clumps together

  • in abnormally high levels.

  • These clumps form plaques that settle between neurons, disrupting cell function.

  • Unfortunately, scientists have had a hard time making mouse models for Alzheimer's.

  • In 1995, researchers thought they'd made a breakthrough.

  • There's a rare, inherited form of Alzheimer's disease in humans,

  • in which people develop symptoms as early as their forties.

  • The researchers genetically engineered a mouse model

  • to have a single gene variant associated with that form of the disease.

  • This mouse, and similar models that followed in the next decade,

  • accumulated plaques in ways that provided researchers with important insight into Alzheimer's.

  • A drug called Aducanumab showed promise in targeting the beta-amyloid protein plaques.

  • Some even called it a holy grail because of how well it targeted the plaques in mice.

  • Unfortunately, the drug failed to work in humans during clinical trials.

  • Scientists aren't sure why yet,

  • but one reason could be because beyond the cellular level, our brains are pretty different.

  • Changes in rodent brains don't necessarily affect their behavior

  • the same way comparable changes affect behavior in humans.

  • It's a similar case with multiple sclerosis, or MS,

  • a disease of the central nervous system.

  • In people with MS,

  • it's thought that the immune system attacks

  • the protective myelin sheath surrounding nerve fibers.

  • This interferes with the communication signals

  • between the brain and the rest of the body, resulting in a wide variety of symptoms

  • including problems with mobility, vision, sensation, cognition, and speech.

  • Since it's most likely an auto-immune disease,

  • it makes sense to study treatments that interfere with the out-of-whack immune response in the

  • bodies of people with MS.

  • That's why scientists in the 80s were interested in IFN-γ.

  • It's a specific type of interferon,

  • which are proteins involved in activating the immune system's defenses.

  • IFN-y showed a lot of promise in mice,

  • so much so that it made it into clinical trials for humans.

  • But, it turns out that our immune systems differ in some important ways from mice immune

  • systems,

  • and the drug ended up worsening patients' MS.

  • Scientists later realized that the mouse model of MS does resemble human MS in terms of symptoms.

  • But the way it actually works in our cells is very different.

  • Similar to other mouse models used to study diseases,

  • scientists can't always get mice to have the exact same disease that happens with human

  • counterparts.

  • Usually, the best they can do is something that looks and acts similar enough to study.

  • In the case of MS, what the mice actually have

  • is something called experimental autoimmune encephalomyelitis, or EAE.

  • Even though EAE mice have provided a lot of insight into MS,

  • there are certain phases of MS that don't happen in an EAE mouse.

  • To date, that same mouse model from the 80s remains the most widely used

  • to study immune disease mechanisms and potential treatments for MS.

  • But one avenue of inquiry is understanding

  • how human MS is different from the mouse model.

  • Our mouse models for infectious disease can be tricky as well.

  • Consider hepatitis B,

  • a viral infection of the liver that can become chronic,

  • especially in younger patients.

  • It can cause serious complications, including cirrhosis and liver cancer.

  • The drug Fialuridine showed a lot of promise not only in mouse models for hepatitis B,

  • but rats, dogs, and monkeys, too.

  • The drug incorporates itself into viral DNA,

  • blocking the viruses' ability to multiply.

  • During the animal model experiments,

  • scientists did know that fialuridine's mechanism isn't unique to viral DNA.

  • It can also affect the DNA of mitochondria,

  • the organelles that cells use to produce energy.

  • But this didn't cause problems in any of the four mammalian models they studied.

  • So clinical trials in humans moved ahead in 1993.

  • But to researchers' surprise,

  • seven out of fifteen people enrolled in the trial developed liver failure,

  • and tragically, five of them died.

  • It turns out that human liver cells have a unique protein

  • that actually helps drugs like fialuridine get into the mitochondria.

  • Making it toxic to humans, even when other mammals aren't bothered.

  • Before testing it on humans,

  • scientists figured that since fialuridine couldn't get into the animal models' mitochondria,

  • it would be unlikely to do so in people.

  • There was a silver lining, though.

  • Realizing that this unique protein affects how drugs like fialuridine work

  • have led to some breakthroughs,

  • including creating a woodchuck disease model for hepatitis B.

  • Then there's tuberculosis,

  • a potentially severe infection of the lungs caused

  • by a bacterium called Mycobacterium tuberculosis.

  • Patients typically have to take a whole battery of antibiotics to combat it,

  • since this bacterium is really good at becoming resistant to the drugs used to treat it.

  • The TB bacterium and its relatives are really good at infecting all kinds of animals

  • including some non-human primates, elephants, guinea pigs,

  • some birds, and even some marine mammals.

  • So animal models ought to be a slam dunk.

  • And there have been valuable insights into tuberculosis from animal studies

  • including using guinea pigs to study airborne transmission,

  • and rabbits to study a specific form of TB that happens in the upper section of the lungs.

  • But mice in particular don't seem to work.

  • because some vertebrates, including mice,

  • are up to a hundred thousand times more resistant to the toxins produced by bacteria than humans.

  • Scientists think that might have something to do with differences

  • in how our immune systems respond to infection and inflammation compared to mice.

  • Even though our bodies use a lot of similar processes and substances in our immune responses,

  • they way those parts work as a whole can look really different between mice and people.

  • So scientists who work with mouse models to study specific infectious diseases

  • try to be cautious in interpreting their results.

  • Sometimes, the whole issue with a study being in mice,

  • not in humans, crops up in research on the safety of certain substances that we're

  • exposed to or ingest.

  • Sometimes mouse studies even lead to removing substances from the market for human consumption,

  • just to be safe.

  • Or in this case, rat studies.

  • That's what happened with saccharin,

  • the artificial sweetener known for its iconic pink packets.

  • Rats who were fed this artificial sweetener

  • ended up with bladder cancer in studies in the 1970s, and everyone freaked out.

  • And it's not hard to see why.

  • News stories reported that men who used saccharin or artificial sweeteners

  • had a sixty percent higher chance of developing bladder cancer than those who don't,

  • even though this study was in rats, not humans.

  • It's no wonder that Canada quickly banned saccharin.

  • It turns out that rats process saccharin differently than humans.

  • When rats consume it at high enough doses,

  • it forms crystals in the urine, which harm bladder cells and induce tumor formation.

  • Oh, and also,

  • these rats were fed saccharin in their drinking water

  • at the highest palatable dose for every day of their short lives.

  • Which is probably Way more than a human would ever eat.

  • A study published in 1998

  • gave monkeys saccharin at five to ten times the allowable daily intake for humans,

  • and didn't find the same issue.

  • Subsequent research and studies that looked at outcomes in humans who consume saccharin

  • and other no-calorie sweeteners

  • failed to find higher rates of bladder cancers,

  • in people of all genders.

  • The U.S. National Institute of Environmental Health Sciences

  • removed saccharin from its list of known human carcinogens in 2000.

  • Sixteen years later, the Canadian government followed suit,

  • lifting its restrictions on the sweetener.

  • One cutting-edge area of study when it comes to human health is the microbiome

  • the trillions of bacteria and other microbes that live in each of our bodies.

  • Scientists are pretty certain that the microbiome has an effect on our health.

  • They also know our diet and environment can influence the makeup of these microbial communities.

  • For instance, fecal microbiota transplantation

  • has been increasingly used to fight off hard-to-treat infections in humans.

  • But scientists are still figuring out how fecal transplants might help restore a healthy

  • microbiome following a round of antibiotics or chemotherapy,

  • both of which can take a toll on these little critters.

  • A study published in 2018 showed promising results in mice treated with chemotherapy

  • or antibiotics.

  • The fecal microbiota transplants helped restore their microbiomes.

  • These results are interesting,

  • but it's also worth mentioning that genetic differences from mouse strain to mouse strain

  • seem to have a significant effect on microbial composition.

  • Whereas in humans,

  • scientists believe our environment plays a much bigger role than our genes.

  • So it appears we can't directly apply results from microbiome experiments done in mice to

  • human health.

  • There are some developments in the pipeline to tackle this problem, though.

  • For example, researchers at the U.S. National Institutes of Health have developed wildling

  • mice,

  • which retain their useful laboratory genetics --

  • while exhibiting the microbial characteristics of their wild counterparts.

  • The thinking is that the immune responses and microbiomes of wild mice and humans are

  • likely shaped in a similar way

  • through contact with microbes in real life.

  • Mice aren't humans.

  • When it comes to laboratory test subjects, they're much /better/ than humans.

  • They're easy to genetically manipulate, and they breed fast.

  • So scientists can look at the effects on many generations of mice

  • in the time that a human takes to learn how to sit up and crawl.

  • And in all fairness, the examples here are the odd ones out.

  • Health research done in mice really has saved human lives.

  • So we'll keep them around until something better comes along.

  • But it's a good reminder --

  • if a study's done in mice,

  • don't expect it to apply to humans right away.

  • Thanks for watching this episode of SciShow,

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