Mice as discovery driver or how to be small, but help achieve great things

Mice (17th century- current)

Some find them cute, some find them repulsive, and science finds them useful. Mice have been a model organism for a bit over a century and is by far the most used nowadays. Let’s find out what these little creatures did for scientific discoveries and learn cool facts about them at the same time. 

Resources:

https://www.nature.com/articles/s41593-021-00849-x

https://www.labome.com/method/Laboratory-Mice-and-Rats.html

https://www.sciencedirect.com/science/article/pii/B9780128165737000067

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3790571/ 

Cool facts: https://www.yourgenome.org/facts/why-use-the-mouse-in-research

Video: https://www.nytimes.com/2021/05/25/science/optogenetics-brain-social-behavior.html

Example failed animal trial: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964774/ 

Micronucleus test: https://en.wikipedia.org/wiki/Micronucleus_test 

Transcript

The Mouse as model organism

Some find them cute, some find them repulsive, and science finds them useful. Mice have been a model organism for a bit over a century and is by far the most used nowadays. Let’s find out what these little creatures did for scientific discoveries and learn cool facts about them at the same time. 

First tho let’s understand what a model organism is actually. This term is used to describe non-human species in which scientists can model and research different biological processes and phenomena. It can be from anatomical and medical studies, down to molecular mechanisms. These species are usually easy to maintain, and their genetics and characteristics can be manipulated. They may also be studied to further understand evolution, especially when they represent pivotal points in the evolutionary tree. All in all, they were the key for many revolutionary discoveries which led to tremendous improvement in life expectancy and quality for the human species.

The mouse is also the most popular among the wider public. Everybody has heard or seen cool or crazy experiments that have been done with their help. But have you ever wondered why all the pictures with lab mice portray mostly white mice or why they were chosen as a primary animal model in the first place? 

Well, the lab mouse or Mus musculus in its Latin name, has been studied since the 17th century, when William Harvey used them to study reproduction and circulation. What makes them great is the fact that have high reproductive rates (gestation period is just 10 weeks), short lifespan (every year is equivalent to 30 human years) and they are from the same clade as humans, meaning that we do share many of the functional genes and biological processes. Many inbred strains have been created which have as little genetic variance as possible. There are characteristics that differ among the strains, so depending on the goals of the experiment or trial there needs to be a careful selection before its start. Some strains are more prone to some disorders or diseases or display different behavioural patterns. These strains have been created at the beginning of the 20th century by the Abbie Lathrop, Clarence Cook Little and William Ernest Castle. But why are so many of the white? The prevalence of albinism among laboratory rodents is because many of the earliest established strains were albino, and also albinism is an easy selection marker in the early days. The lack of pigment is due to a mutation in an enzyme which results in decreased amount of melanin.

The whole genome sequencing of the mouse was finished in 2002, with 3500 million base pairs and 20 pairs of chromosomes. Although their genome is around 10% smaller than ours, they have 3 thousand more protein coding genes.

What are they useful for tho more concretely?

Genetic conditions

Coolest part about this model is that you can design genetic tools to switch genes on and off, knock them out completely or put them into overdrive, as well as inducing mutant versions for the gene of interest. You even Select the time and cell or tissue when this is happening. Or if you are studying a congenital mutation, design a mouse to carry it and in this manner you can observe its effect on the development of the mouse and its later life. Numerous genes have been tested this way to determine how they influence life span, life quality, the proclivity to different diseases like heart issues, neurodegenerative, obesity, diabetes and so on. But what is even cooler is the ability to study polygenic disorders in mice, such schizophrenia or autism spectre disorder. Given their complexity it can be extremely difficult to determine how many genes play a role, how they may or not interact or to what degree, and this all is made possible through mice studies.

There are many ways to design these mice, but recently the one that seems to get more and more traction is the Crispr/Cas9 which has a opened a whole new world of possibilities for researchers. That is because you can introduce virtually any mutation on any genetic background, meaning that you don’t have to rely so heavily on cross breeding between different mouse strains or changing the genetics through more complex and time consuming methods. An example is the strain that suffers from spontaneous Type 1 diabetes which got a mutation through Crispr in a key gene that has been strongly correlated with diabetes in people. The resulting mice showed increased autoimmune diabetes, this underlying the connection of inherited characteristics and environmental factors when it comes to diabetes and pointed towards exploring this correlation closer. Narrowing the pool of possibilities is crucial in research and this example illustrated that nicely.

Understanding molecular mechanisms in health, prevention and disease

Now, there different ways in which one can study molecular mechanisms in mice through gene expression control. There some really cool systems out there that use different triggers, such light or specific drugs. You can also choose a tissue or specific cell type, as well the time when the gene should be driven. In this manner, many functions of the cell, tissues and even whole bodies can be studied.

I’ll give you an example that involves optogenetics, or using the light as a trigger. There are mice lines that have been engineered to have specific cells sensitive to light which will turn off/on genes when subjected to a beam of light. It can also be designed to have different responses to different kinds of light (like blue, red, etc), making it even more versatile. In 2021, a student at the Nortwestern University, Mingzheng Wu, implanted blue light leds in the prefrontal cortex of two mice which had neurons sensitive to light in a specific part of the brain tight to social behaviour. Then he put them together in a box and at first the mice were reluctant to interact with each other. Mr. Wu switched on the blue light in the wireless implant and fired up the target neurons. In a matter of minutes, the mice started to interact with each other like they’ve been friends forever. There is also a video of the experiment, I’ll link it in the description. It was preeetty impressive.

Drug development

 Let’s move on to the less pleasant. Part of drug and substance discovery, validation and approval is tests on mice. While it makes sense to a certain degree, it’s getting more and more evident that there is a dire need to transition to better fitted testing models. There isn’t a certain agreed upon number of false positives for example, but one figure I found released by the German Medicine authority said that between 25- 36% of all the tested substances came out false positive, which extremely high. Hartung et al. wrote in 2008: “The question might, however, be raised whether mutagenicity in human cells should be ruled out at all by an animal test. A genotoxic effect in vitro shows that the substance has a property, which could be hazardous. Differences in the in vivo test can be either species-specific (rat versus human) or due to kinetics (does not reach the tissue at sufficiently high concentrations). These do not necessarily rule out a hazard toward humans, especially in chronic situations or hypersensitive individuals. This means that the animal experiment may possibly hide a hazard for humans.”

Or even worse, false negatives. In one famous case in UK in which a new antibody therapy passed the animal trials, all 6 human subjects that received a 500 hundred smaller dose than the mice faced life threatening side effects. That is not to say that all animal testing is useless, but that there needs to be more awareness and not only to spare animals from unnecessary tests, but also demand better human specific tests being developed. Hopefully, more resources will be allocated for finding them in the future. And the good news that it is already happening. New gentotoxicity tests are arising based on human derived cells or mouse derived cells that can be collected without killing the animal. One of those is the micronuclei test which consists of subjecting bone marrow or peripheral blood to the tested compounds and analysing the cell’s nucleus after a certain amount of time to check for damage. It is an extremely successful assay that has been approved by the Organisation for Economic Co-operation and Development.

This was just a brief introduction of how cool of a model mice are in the world of science, I hope you found it interesting and got some new pieces of trivia to throw around at parties. They also work as pick up lines. Example: hey girl are you a lab mouse? Cause I want to test my charm on you.

I swear it worked, let me know if it worked for you too!

Resources:

https://www.nature.com/articles/s41593-021-00849-x

https://www.labome.com/method/Laboratory-Mice-and-Rats.html

https://www.sciencedirect.com/science/article/pii/B9780128165737000067

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3790571/ 

Cool facts: https://www.yourgenome.org/facts/why-use-the-mouse-in-research

Video: https://www.nytimes.com/2021/05/25/science/optogenetics-brain-social-behavior.html

Example failed animal trial: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2964774/ 

Micronucleus test: https://en.wikipedia.org/wiki/Micronucleus_test