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Mouse Models in Human Diseases


Image is courtesy of Wix.

Mouse Models


Mouse models are often used to perform biomedical research on human diseases. This includes providing information about genetic bases of parasites, its metabolism, lifecycle, reactions for different drugs, and potential side effects for drugs.


There are many differences between humans and mice as they are two distinct species that evolved individually in different environments. One significant difference is size, which affects metabolism and other size-dependent components such as thermoregulation, nutrient demand (mitochondrial density), and brown fat deposits. The metabolic rate of one gram of tissue in a mouse is around seven times that of humans. Difference in metabolic rate leads to a difference between humans and mice in level of metabolic activity in organs such as the liver, kidney, and bones. Differences in brown fat deposits make the fatty acid composition in mice cell membranes different from humans.


Given these differences, mouse models should be chosen carefully, and researchers should not be surprised if a result from a mouse model is inconsistent with results from clinical trials. For example, the case with anticancer drug Endostatin showed it was effective in treating cancer in mice, but not so much in humans.


However, there must be reasons as to why mouse models are still so commonly used in experiments. Even though they have separately evolved into two distinct organisms, there are still some genetic components that are very similar between humans and mice. Another benefit of mice is its availability; they are easily bred and maintained in laboratories. Furthermore, mice have the ability to be humanized, by manipulating mouse genes using various techniques of transgenic, knock-in and knock-out, which makes mice react even more similarly to humans when faced with disease. Mouse models have tremendously enriched our understanding of human biology and parasite biology. They are used to research diseases such as Hepatitis B, and Malaria, and stem cell research with mouse models are used to tackle various conditions, these include stoke, Alzheimer’s disease, and cystic fibrosis.


Example: Mouse Model for Malaria Research


Malaria is a disease that is transmitted through mosquito bites, travels through blood, and reproduces in the liver. It is caused by the parasite Plasmodium Falciparum (P. falciparum), and some of its common symptoms include high fever, shaking chills, anemia, and jaundice. Malaria research uses mouse models to perform genetic crosses to better understand how P.falciparum lives, and how they react to different drug use to treat malaria. Image is courtesy of Harvard.Edu.


One of the reasons why mice are used for studying human diseases like malaria is because they are severely immunodeficient, and therefore unable to reject foreign tissues. In this case with malaria, it is the xenograft of human hepatocytes, or liver cells. This makes it easy to humanize a mouse’s liver by transplanting human hepatocytes. Before the mouse is injected with human xenografts, the number of their native hepatocytes will be artificially reduced, to allow for human hepatocytes to repopulate its liver. After the process, the mouse will become a chimeric mouse, meaning humanized.


In a specific model called the FRG model, humanized mouse liver cells can be extracted and transplanted into other mice to humanize them, increasing the number of mice that can be humanized from one human donor. Although entire humanized metabolic systems cannot be built inside the mouse, a humanized liver already makes the mouse and mouse model valuable enough in malaria research. This is because previously, genetic studying relating to P.falciparum have only been done by infecting primates like chimpanzees, and were only able to investigate the erythrocytic stage of the parasite, while it was in the blood. The mouse model offered for studies to be done in the liver stages of the parasite.


Ethics


Because mouse models for human disease research is performed by humans on other organisms and these experiments have no benefit to the mice, there will inevitably be ethical debates surrounding this, as do all animal models used in any biomedical experiment. Jeremy Bentham, a British Philosopher from the 1800s, described an action to be ethical if it can provide benefit to society; it is more ethical if it can provide more benefit, and he believed this principle should be applied to all lives with sensitivity. Sensitivity, as he defines it, is a question of if the being can suffer. As all animals can suffer the same as humans, this principle should also be applied to animals.


There are 3 Rs discussed by Zoologist William M.S. Russell and Rex L. Burch when trying to protect animals in biomedical research: replace, reduce, and refine. This originates back to 1959.


Replacing animals in in vivo experiments with alternative in vitro methods allows animals to suffer the least, and thus avoids ethical issues. In vivo methods are experiments done inside whole living organisms. In vitro methods are procedures carried on living organisms outside of their normal biological settings—for example, removing hepatocytes from a mouse’s body and experimenting in test tubes. Another alternative of animal models is simulating possible results using computer algorithms.


Reduce means reducing the number of animals used in experiments. This calls for more efficient experimental procedures and higher quality statistics that can represent a larger population with a small sample size. Refine means to alter experimental procedures so there is least pain felt by the animals. This includes making sure animals do not get infected due to operative wounds, and Anesthesia.


References


Justice, M. and Dhillon, P.. (2016). Using the mouse to model human disease: increasing validity and reproducibility. National Center of Biotechnology Information (NCBI). Retrieved February 1, 2021 from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770152/

What is a mouse model? The Jackson Laboratory. Retrieved February 1, 2021 from https://www.jax.org/why-the-mouse/model

Our mice, our hope. The Jackson Laboratory. Retrieved February 1, 2021 from

https://www.jax.org/news-and-insights/stories/medical-progress#:~:text=Stem%20cell%20research%20in%20mice,cell%20depends%20on%20mouse%20models.

About Malaria. Center for Disease Control and Prevention (CDC). Retrieved February 1, 2021 from

https://www.cdc.gov/malaria/about/faqs.html#:~:text=Symptoms%20of%20malaria%20include%20fever,loss%20of%20red%20blood%20cells.

Strom, Stephen. Davila, Julio. Grompe, Markus. 2011. Chimeric Mice with Humanized Liver: Tools for the Study of Drug Metabolism, Excretion, and Toxicity. NCBI. Retrieved February 1, 2021 from

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3136240/

Miziara, Ivan. de Matos Magalhães, Ana. Santos, Maruska. Gomes, Érika. de Oliveira, Reinaldo

2012. Research ethics in animal models. Science Direct. Retrieved February 1, 2021 from

https://www.sciencedirect.com/science/article/pii/S1808869415300203



Article Author: Ivy Sun

Article Editors: Stephanie Sahadeo, Sherilyn Wen

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