Of mice and (hu)men…
November 28, 2008 by Caroline Brandon
What do mice and humans have in common? It turns out…a heck of a lot. In fact, humans and mice have quite a few common genes that play similar roles in the development of our major organ systems, including nervous, cardiovascular, immune, skeletal, and endocrine to name a few. Moreover, the cells of mice and men are so similar that we can interchange genes between mice and humans quite frequently, and we can introduce genetic alterations into mouse cells found in human disease and observe the consequences.
One of the most common ways to study mammalian development and diseases such as cancer and other genetic disorders is to modify the mouse genome and then study the effects of these modifications. One advantage is that mice have short life spans and reproduce extremely quickly, as frequently as every nine or so weeks. This provides researchers with a tool to study these effects over many generations and allows us to understand development and disease from the beginning, and not solely at their endpoints.
Various types of mouse models exist for a plethora of diseases from cancers to genetic disorders such as Huntington’s and Alzheimer’s disease, to behavioural disorders such as anxiety and alcoholism. There are several ways to create these mice; you may ‘knock-in’ a gene, alter a gene, or ‘knock-out’ a gene. All of these methods require that the gene of interest be modified in the mouse embryonic stem cells so that the subsequent mouse that develops carries the modification in every cell. The resulting phenotype (a fancy scientific word for characteristic) may resemble the symptoms of human disease and thus may be used as a model for treatment discovery.
How does this apply to stem cells, other than the brief cameo of embryonic stem cells just mentioned? Well, if we suspect certain genes to be important in stem cell regulation in various tissues, we can then manipulate these genes and study the effects on stem cells in the mouse, answering questions about tissue and organ development, tumour initiation, and diseases that are thought to arise from stem cell populations gone wrong.
One of the best ways to understand human disease is to transplant human cells into mice. These experiments require special mice that have been bred to lower or eliminate their immune system (like the bubble-boys of mice), essentially allowing them to host human cells without mounting an immune attack on the cells. Using these mice, researchers around the world were able to prove the isolation of cancer stem cells (including brain cancer stem cells!!), understand major genetic alterations associated with human cancers, and test chemotherapeutic agents against human cancer tissues as a preliminary step to clinical trials.
That said the genetics behind human diseases are generally far more complex. However, thanks to mice, we’ve made great strides in understanding our development, how and why we succumb to disease and what we can do to treat it. So next time you see a mouse scurry across your floor, offer it cheese…they’ve earned it!
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Rett Syndrome and induced Pluripotent Stem cells goes “Green”
June 17, 2009 by Aaron Cheung
Stem cell researchers at The Hospital for Sick Children have now devised a method, reported in the scientific journal Nature Methods, that will facilitate the generation of induced Pluripotent Stem (iPS) cells. I have previously blogged about the promise of iPS cells (see related articles). iPS cells are cells which have been reprogrammed from a differentiated somatic cell (such as your skin cells) to a pluripotent stem cell (like an embryonic stem cell, only that you don’t need to use embryos!). The generation of iPS cells is inherently very rare which occurs at a frequency of about 0.01% meaning you can generate about one iPS cell line out of hundred thousand cells. Out of which, many lines fail to satisfy the different rigorous tests necessary to be given the prestigious name of “iPS cell”.
A group led by Dr. James Ellis, and lead author Dr. Akitsu Hotta, at The Hospital for Sick Children has generated a reporter, named EOS, that will facilitate the generation of iPS cells for both mouse and human. The reporter has DNA elements (called promoters) that will drive the expression of a fluorescent protein (GFP) and an antibiotic resistance gene (puromycin) that will only turn on in pluripotent stem cells, but remain off in differentiated cells. Therefore, scientists can now generate iPS cells from different sources and the iPS cells will literally “light up with a green colour” once reprogramming has been achieved. Furthermore, by adding puromycin to your culture, it will keep the iPS cells in a pluripotent state as iPS cells will normally spontaneously differentiate.
To demonstrate the applicability of EOS, Ellis also derived iPS cells from patients who have a neurodevelopmental disorder called Rett Syndrome. Rett Syndrome is an Autism Spectrum Disorder which affects almost exclusively females at an incidence of 1 in 10,000 and is one of the leading causes of mental retardation in girls. These Rett Syndrome iPS cells were green when placed under a fluorescent microscope and Ellis demonstrated that neurons can be generated from these Rett Syndrome iPS cells, the cell type affected in Rett Syndrome.
In conclusion, the EOS reporter will facilitate the generation of iPS and will be particularly useful for new labs going into this rapidly developing field. Furthermore, Rett Syndrome iPS cells that were also generated in this study will be invaluable for future drug screens that may be beneficial to those with Rett Syndrome.
Article:
Hotta, A. et al. Isolation of human iPS cells using EOS lentiviral vectors to select for pluripotency. Nature Methods 6, 370–376 (2009).
Related articles:
Breakthrough of 2008 – Reprogramming
A New Era for Disease Modeling and Drug Screening
Some of our experts
Stem Cell Origins
Cancer stem cells
Stem Cells and the Nervous System
