New mouse deLIVERy system

Original article for free at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2768028/?tool=pubmed

Humanising mice!

Animal models have been a huge help in medical science. Almost everyone in the world today has benefited from medicines and surgical procedures all researched first in animal models. However, one of the main problems with animal models is that they’re not human, which means that some diseases don’t infect them in the same way (or at all), drugs don’t interact the same way as they would in humans (e.g. penicillin is very toxic to guinea pigs, but mostly harmless to us) and all the rest.

To combat one aspect of this problem, many groups from around the world have worked together to develop a strain of mice with human livers. Development of these mice was a ridiculously complex task and each step of development came from a different lab.

Previous crossbreeding experiments had failed... (Picture taken by Thomas Tu)

Making room

Firstly, they had to get rid of all the liver cells from the mouse. To do that, these scientists used the properties of Urokinase-Plasminogen Activator (uPA).

UPa, as its name suggests, activates plasminogen (PlasGen). PlasGen is the precursor for an enzyme called plasmin (a plasmin generator, pretty logical). Plasmin is a protease, a group of enzymes that cut up specific proteins. Plasmin cuts up a range of proteins, including those that make up blood clots and proteins that hold your organs together.

So wherever you have uPA, a lot of PlasGen is activated, turned into plasmin. If you inject uPA into a mouse, all you’ll get is a mouse that bleeds a lot. This is because uPA will stay in the blood and activate PlasGen there, which will cut up any blood clots. This is because the vessel walls are tight and will not let any uPA, PlasGen or plasmin through to access the liver cells. So let’s inject it right into the liver and get bits of liver falling apart and dying. However, most of the plasmin will stay where you injected it because it’s not in the blood to be transported throughout the organ, so you won’t get rid of all of the liver cells. Paradox!

Using gene manipulation, scientists put the gene for uPA in every cell of the mouse. Now if you make uPA in every mouse cell, you will just get a puddle of mouse. The clever way to get around this is to put uPA behind a liver-specific promoter.

Roll up, roll up!

All of your cells have the same DNA in them; the same DNA is in a brain cell, a liver cell and a bone cell. What makes them look and act differently are the specific genes are activated in each of these cell types. The way that cells do this is by using genetic switches called “promoters”. Promoters are basically regions of DNA that say activate the gene that is next to me. So a way (certainly not the only way) that the cell makes sure to make activate all the genes it needs is to put the same promoter next to all of the required genes. The scientists used genetic manipulation to put uPA next to a promoter that is activated only in the liver. So all the liver cells are producing uPA, making the entire liver fall apart and die.

Now it turns out if you inject human liver cells into these mice, the human cells can attach to sites in the liver of the mice and start replicating. Now the liver is special in that it is the only internal organ that can replace itself. Studies have shown that liver cells can replicate over 50 times , so that 1 cell can eventually produce at least 1125899906842624 cells, enough for an entire new liver. As a side note, this means other tricks will have to be implemented to swap in human organs for mouse hearts, lungs, kidneys, etc., all the internal organs that don’t have this regenerative property.

Anyway, back to the mouse liver. Since the human cells are not churning out uPA, they do not die like the mouse cells. After a while, the human liver cell population replaces the mouse liver cells. Some of you more astute readers may find a problem with this; the human cells are definitely not mouse cells, meaning the mouse immune system will develop a response against them. In normal mice, this would be a problem, but the scientists thought about this and made this manipulation in SCID mice.

The SCIDs are alright

SCID stands for Severe Combined Immunodeficiency, meaning that the immune system  does not develop at all in these mice. SCID humans (untreated) become completely vulnerable to all sorts of infections and have been made into pop references (cf. Seinfeld’s bubble boy). In this case, SCID mice are unable to mount an immune response to the human liver cells and so soon the mouse liver is completely populated with human liver cells.

So, any drugs given to these mice would be processed in the detoxifying liver exactly as it would in a human. Also, any pathogens that use the liver as an infection site (e.g. Hepatitis B) could infect these mice as it would a human (although, without an immune system, long term infection studies are not very informative). Indeed a few studies have been published containing these types of experiments, giving us better insights on the liver’s involvement under various conditions. It seems the days of experimentally infecting people are winding down…

TT

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4 Comments

Filed under Thomas' Corner

4 responses to “New mouse deLIVERy system

  1. Uwe

    love the pic, I could have told you that the cross breeding was never going to work, because the mice you get are sterile otherwise you would never have to buy a new mouse.
    Interesting article although as you pointed out the use is limited for looking at liver infection. Still probably a great tool looking at drug effects and detoxification in the liver. Not sure if this will be a problem since soon they won’t need desperate Uni students to do drug trails. Damn progress another job prospect gone.

    • thomastu

      Now, now Uwe. There’s still a great deal Uni students can do: they still need people to produce cerebral-spinal fluid or sperm/ova; they haven’t bred rats that can serve people at Macca’s yet; and there’s always slave labo- I mean, a PhD. Life Impact!

      TT

  2. roflmao on the pic! Congrats on the article in the ‘Tiser today too, looked great don’t you think?

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