This is one of those things that isn’t really related to neuroscience, to weird science, or to any of Sci’s normal science. Really, it was just something Sci found (in various places), and thought was really awesome. Cause it is!
BEHOLD! The INCREDIBLE HEALING MOUSE!!!
For those who know about working with rodents, it looks like a rat, don’t it? It’s a mouse! But it looks like a rat because these dudes are some big boys. This is an MRL mouse, which stands for ‘Murphy Roths Large” (Sci can certainly believe the large). They were originally bred as a strain of laboratory mice, used for autoimmune studies (things like Lupus).
But these MRL mice might be the next big thing in wound healing. The story of their discovery is interesting on its own. The story of HOW it happens could change the world.
Bedelbeava et al. “Lack of p21 expression links cell cycle control and appendage regeneration in mice” Proceeding of the National Academy of Sciences, 2010.
(Ok, I’ll admit I’m a little behind on this, apparently the big news broke in February or March. But still, I found it!)
And it all starts with a little ear piercing.
As you might be aware, laboratory mice (and rats!) are big in some types of research. Although animal research is only a small percentage, 95% of animals used in research are rats and mice. They are usually bred specifically for research purposes, and some strains are bred with specific genetic abnormalities that are very close to diseases in humans.
Of course these mice are housed, with their buddies (no more than 5 to a cage generally because you don’t want crowding, but you want mice with buddies, because lonely mice are unhappy mice), in cages. And somehow you have to tell them apart. And it’s tough when they’re an inbred strain like the MRL, and all…look like each other. With other types of mice, like this one:
(The C57 Black 6J, a super common research mouse)
The mice are so closely related as to be almost genetically identical. And it’s REALLY hard to tell them apart. When you need a whole cage of mice to tell apart, and you need it for a long time, it’s time for some ear piercing. It’s very fast, done when they are young, and produces very little pain and usually no bleeding at all. You can carefully position the holes on one side or the other, on the top of the ear or the bottom, and then have a table so you know who is who.
So they had these MRL mice, they were looking at autoimmune disorders, and the mice had pierced ears.
And then they DIDN’T. Most likely a post-doc got yelled at something fierce. Possibly a grad student. The mice had pierced ears again.
And then they DIDN’T.
The earholes closed up within DAYS, and not only did they close up, there was no scar tissue to tell where they had been! There were even new blood vessels and hair follicles in the region! Check it out!!
On the left is a regular C57 mouse. On the right is an MRL mouse. Crazy, huh?! The C57 mouse shows some healing (which you would expect), but nothing like the MRL. And it was even better than that. These mice can not only close up ear holes, they can partially regenerate things like lost toes, which is something that before we thought only sponges, planaria, and salamanders could do (humans can regenerate some things, like parts of our livers, damaged muscle, etc, but LIMBS are way beyond us).
And of course this got the researcher’s attention. This could be a really big thing. If we knew how these mice healed up, and could maybe get something similar to happen in humans, who knows what we could do!
(Momentary break for visions of MAD SCIENCE swarming in Sci’s little head)
But of course first you have to know how it works.
Let’s talk about the cell cycle.
The cell cycle can be divided into four main phases and one side-ish phase, shown here:
G1 is the phase in which all the organelles and stuff are duplicated in preparation for cell division. The S phase is the main phase when the DNA is duplicated. G2 is the chance for the cell to double check, to make sure no errors have been made in duplication. Then of course, there is mitosis.
But at each step of the way, there are proteins which regulate whether or not the cell is allowed to move on to the next step. If the cell should not move forward (too many mutations to continue, for example), the cell will kick into a stage called G0, which is also called scenesence.
And two of the proteins which acts as a gatekeeper for whether the cell can go forward or not are p21 and p53.
p21 (aka WAF1 aka cyclin-dependent kinase inhibitor 1 aka CDK-interacting protein 1 aka why can’t we all just call it Bob or something?) is a rather complicated protein, but we’re going to simplify here. p21 is a gatekeeper to stop a cell from going to G1 through S phase.
p53 is better known as a “tumor suppressor gene”, but it also controls whether a cell can go from the G2 phase to the mitosis phase.
So if you have high levels of p21 (or normal levels) a lot of cells won’t go forward to the next stage. Conversely, if you have high levels of p53, a lot of cells WILL go through mitosis. They act in opposite directions.
High p21 = no S phase for YOU!
High p53 = MITOSIS PARTAY.
And what the authors of this paper found was that, in the ear of the MRL mouse (which did all the healing) as WELL as in the ears of other “healing” mice, the mice had HIGH p53 and LOW p21. This means that, since p21 is LOW, the cells proceed through the S cycle, and since p53 is HIGH, they keep right on through to mitosis.
It’s a cell dividing party right in there.
Not only that, they found that these cells liked to STAY in the G2 phase when they weren’t dividing, which is a characteristic of cells that like to divide a lot, like stem cells, and of healing cells in parts of our bodies than can regenerate, like the liver.
This means that the cells of these mice are capable of responding to injury by lots of cell division, healing up the injury. The authors also found that if you knocked out the gene for p21 entirely, you got a similar effect, showing that it may be the low p21 that is responsible for the healing in these mice.
There’s lots of possibilities for what to do with this. If we could maybe learn how to decrease p21 in specific parts of an injured, normal mouse, we might be able to produce healing in that part only (and then, of course, we might be able to do it in humans). This could end up in HUGE advances for the way we heal wounds now, and for HOW those wounds heal (not to mention that unadvisable piercing you got yourself when you were 18 and now really want that hole and scar gone…).
However, we shouldn’t be rejoicing just yet. Cells have these checkpoints with things like p21 for a REASON, you know. The reason is to make sure that cells which have DNA damage don’t go on. You don’t want DNA damage collecting. And sure enough, when the scientists looked, they saw that the MRL mice had increased DNA damage in the ears that were healed, along with increased apoptosis (a controlled cell death which occurs when a cell is too damaged to function). The apoptosis is good, because it means that damaged cells aren’t staying around, but DNA damage is not a good thing. The right DNA damage, in the right places, and causing uncontrolled cell division and growth, is what we call cancer. So while these mice have increased healing, they may ALSO be more susceptible to cancer, so more research is going to need to be done to figure out if this ability is worth harnessing, and if we can control it to use in wound healing for humans and animals.
Bedelbaeva K, Snyder A, Gourevitch D, Clark L, Zhang XM, Leferovich J, Cheverud JM, Lieberman P, & Heber-Katz E (2010). Lack of p21 expression links cell cycle control and appendage regeneration in mice. Proceedings of the National Academy of Sciences of the United States of America, 107 (13), 5845-50 PMID: 20231440
Filed under: Physiology