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A lot of our videos include the disclaimer "Mice aren't people". But why do we keep saying this, and if rodent studies aren't effective, why do we keep using them?

Hosted by: Stefan Chin

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Sources:

Intro:
https://www.genome.gov/10005834/background-on-mouse-as-a-model-organism

Alzheimer's disease:
https://www.nia.nih.gov/health/what-happens-brain-alzheimers-disease
https://www.nature.com/articles/d41586-018-05722-9
https://www.biospace.com/article/a-look-at-biogen-s-big-bet-on-the-holy-grail-of-science-and-mdash-alzheimer-s-/
http://investors.biogen.com/news-releases/news-release-details/biogen-and-eisai-discontinue-phase-3-engage-and-emerge-trials
https://www.nature.com/articles/s41586-019-1506-7

Multiple sclerosis:
https://medlineplus.gov/multiplesclerosis.html
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4154595/
https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(87)92863-7/fulltext
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586507/
https://www.degruyter.com/view/j/revneuro.2019.30.issue-1/revneuro-2018-0002/revneuro-2018-0002.xml

Hepatitis B:
https://www.cdc.gov/hepatitis/hbv/index.htm
https://www.nap.edu/catalog/4887/review-of-the-fialuridine-fiau-clinical-trials
http://discovermagazine.com/1994/mar/thecurethatkille345
https://www.ncbi.nlm.nih.gov/pubmed/16595656
http://perspectivesinmedicine.cshlp.org/content/5/12/a021451.full

Tuberculosis:

https://www.cdc.gov/tb/publications/faqs/qa_introduction.htm
https://medlineplus.gov/tuberculosis.html
https://www.ncbi.nlm.nih.gov/pubmed/11288517
https://www.ncbi.nlm.nih.gov/pubmed/20819249
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798013/
https://www.jimmunol.org/content/172/5/2731#sec-6

Saccharin:
https://www.nytimes.com/1977/06/19/archives/fda-says-new-canadian-study-reinforces-its-ban-of-saccharin.html
https://academic.oup.com/annonc/article/15/10/1460/170200
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2009921/
https://www.ncbi.nlm.nih.gov/pubmed/9428778
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5591507/
https://www.niehs.nih.gov/news/newsroom/releases/2000/may15/index.cfm
https://www.foodserviceandhospitality.com/health-canada-approves-saccharin-sweeteners-canada/

Microbiome:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4991899/
https://www.nature.com/articles/s41598-018-24342-x#Sec8
https://www.health.harvard.edu/blog/stool-transplants-are-now-standard-of-care-for-recurrent-c-difficile-infections-2019050916576
https://dmm.biologists.org/content/8/1/1#sec-16
https://www.the-scientist.com/news-opinion/mouse-genetics-shape-the-gut-microbiome-more-than-their-environment-66238
https://www.eurekalert.org/pub_releases/2019-08/niod-mc072919.php

Closing:
https://www.nabr.org/animal-research-into-the-worlds-five-deadliest-diseases/

https://commons.wikimedia.org/wiki/File:Neuron.svg


https://commons.wikimedia.org/wiki/File:1FG9_IFNG_IFNG.png#/media/File:1FG9_IFNG_IFNG.png
[ intro ].

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, and thanks to our patrons for making it happen. We really appreciate all of your support. If you want to earn cool perks and help us make great videos, consider joining up at patreon.com/scishow. [ outro ].