The Incredible Healing Mouse

May 10 2010 Published by under Uncategorized

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!

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 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!
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

24 responses so far

  • Paul Browne says:

    That's really interesting. I'd heard of the healing powers of the MRL mouse before but missed this paper identifying altered levels of p21 as being responsible.
    While I agree that it is important to study the effect of reducing p21 on carcinogenesis I'm optimistic that such problems can be avoided or overcome. If a treatment to reduce p21 levels can be administered locally at the site of injury, as is likely to be the case, rather than systemically than the risk of cancer should be much lower. Also you would only need to administer the p21 reducing agent for a short period while the wound is healing, which would not give cancer very long to develop.

  • kjackson says:

    I'm not a scientist, but I'm wondering if this characteristic makes them more prone to tumors or cancer. If the cell that is dividing a lot has bad genes, like some forms of cancer, couldn't that make it much easier for it to divide and subsequently spread throughout the body?

  • Paul Browne says:

    Kjackson, that would certainly be a concern if the levels of p21 were turned downn permanently. In the MRL and p21 knockout mice you do see an accumulation of more damaged DNA than in normal mice, but I don't think that anyone has done (or at least not published) any studies showing how this affects the risk of a mouse developing cancer over its lifetime. Whatever the risk is in mice I'd expect that the risk would be greater in humans because our longer lifespans give more time for damage to accumulate and develop into cancerous cells.
    For this reason I think that any treatment will seek to reduce p21 activity in specific tissues for short periods of time rather than reducing it throughout the body for long periods of time.
    I think we're still quite far from being a nation of Claire Bennets.

  • Kevin says:

    Thanks for writing about this! I saw Dr. Heber-Katz on an episode of NOVA when they had found these mice were healing but really didn't know what was going on yet and I thought it was super cool.

  • Judy Yeo says:

    Actually remember seeing this as a news report and thought it was great, not the re-peircing part though. And frankly reminded me of a cartoon. not sure if anyone remembers this cartoon but there was a cartoon about these 2 lab mice who plotted to take over the world every night . pinky and the brain?

  • Marco says:

    I assume p21 could probably be temporarily deactivated at the site of injury by using a pluronic gel antisense oligonucleotide. I don't know if p21 suppression would lead to an increase in cancer, but the p21 knockout mice were prone to autoimmune disease. However, MRL mice can not regenerate skin wounds - they heal by forming scar tissue. The researchers mentioned that they are looking into ways to temporarily deactivate p21 in hopes that humans could heal without scars, but do the p21 knockout mice regenerate skin wounds or do they scar like the MRL?

  • Lucy Honeychurch says:

    LIMBS are a completely different thing, but pierced ears are no problem for humans.
    Every girl knows that if you don't keep your piercing post in for MONTHS after the puncture, your ear piercing will close in no time. Sometime it will continue to try and close YEARS after piercing.
    So, I'm nonplussed about the ear piercing closing 'phenomenon'. I'd be much more interested to hear about how they regenerate their limbs.

  • Neuroskeptic says:

    There must be a downside, because otherwise all mice would be like these. Being able to regenerate wounds quickly is a survival advantage so natural selection would have given that ability to everyone if it were truly advantageous...there has to be a catch.
    I'd be very surprised if these mice didn't have an increased incidence of tumours. But as others have said a selective p21 inhibitor could be awesome.

  • canuck_grad says:

    True, Lucy ... I had my ears pierced at age 3 and had to have them re-done at age 20 after a couple of years of not wearing earrings. I still have to poke through if I haven't worn earrings for longer than a few weeks.
    BUT look at the size of those holes! And how quickly they healed! Out of curiosity, does anyone know if/how quickly giant ear holes heal in humans? Like these ones:

  • luke says:

    The mouse ear holes were only 2mm, and in the p21 knockout mice they almost fully healed about 28 days later - they didn't fully close. Piercings in humans that large wouldn't close.

  • bigdeal says:

    Regenerative ear holes? Big deal...unless there is a proven human application this isn't news just a waste of time.

  • crickets says:

    @ bigdeal
    how are you supposed to prove a human application without spending some time on it first? only in extremely trivial or recurrent situations is it possible to know that something will be a waste of time before the time has been wasted.

  • eddie_picnic says:

    crickets: I was referring more to the media coverage than the research itself. However, unless the researchers can prove a practical human use it's just wasteful speculation. Read Marco's comment - it's spot on. Deactivate p21 - I know of 3 chemicals that can do it (and the researchers do too). If they are worried about cancer and autoimmune disease then why don't they just create an excisional skin wound on a patient who is already undergoing p21 down regulation (ironically for targeting cancer stem cells). However all they have to do is demonstrate that p21 is behind tissue regeneration by creating a skin wound in the p21 knockout. If that doesn't work then it won't work for humans..If it does work then you might have something.

  • eddie_picnic says:

    whoops i should have mentioned that i posted originally as bigdeal

  • mark says:

    "MITOSIS PARTAY" The best phrase in a science blog ever! Way to make science interesting AND fun!

  • Richard says:

    Could an expert please elaborate on some of the concerns that have been mentioned? Namely cancer and autoimmune risk and if p21 could be suppressed temporarily how it may affect these risks, how exactly it works other than just cell cycle regulation (if that is known), the difference in regeneration between the mrl mouse and p21 knockout mouse (is there more to it that the researchers haven't discovered?). And most importantly - could it work in humans?? I know there is no way to know this until it's tested on humans, but if the mrl mouse doesn't regenerate skin wounds why would they think it would work for humans? Seems like a very basic question, but as a couple people have said if it works in the p21 deficient mice it might work in humans since we also have the p21 gene, but if it doesn't theres no chance in hell. It really sucks to have a serious interest in this type of research, as it could significantly help a lot of scarred people who are suffering physically and emotionally, and not get all the details. I get the feeling like we're left in the dark. In 1997 a leading wound researcher said they hoped to be able to regrow hair follicles and sweat glands in 5 years and achieve scarless healing in 10. Even the author of this research said this in late 2006:
    "I believe that the day is not far off when we will be able to prescribe drugs that cause severed spinal cords to heal, hearts to regenerate and lost limbs to regrow. People will come to expect that injured or diseased organs are meant to be repaired from within, in much the same way that we fix an appliance or automobile: by replacing the damaged part with a manufacturer-certified new part. Advances in heart regeneration are around the corner, digits will be regrown within five to ten years, and limb regeneration will occur a few years later. Central nervous system repair will occur first with the retina and optic nerve and later with the spinal cord. Within 50 years whole-body replacement will be routine."

  • Scicurious says:

    Richard: well, if you want an expert to comment, they're going to have to come by the blog first! Since I don't see any, I'm about what you'll get, I'm not an expert, I just read the paper.
    I've been looking into the literature, and here's the deal as far as I can tell:
    1) MRL mice regenerate better than others
    2) This appears to be due to low p21 and high p53.
    3) p21 deficient mice heal similarly (that's for eddie), so yes this could end up with practical use.
    4) given the above, if we were to decrease p21 we might be able to speed wound healing.
    5) So yay.
    6) BUT, p21 is a cell cycle regulator and might have significant implications for cancer.
    7) HOWEVER, no one has apparently studied this stuff yet in these mice.
    So we don't KNOW if these mice are more susceptible to cancer or if they are compensated for by other things. More research required. However, keep in mind that these days, we mad scientists can change gene expression in tiny areas of tissue using a technique called viral-mediated gene expression. We have been able to do this in rodents (and I think in monkeys), but have not yet worked on it in humans. It's possible, therefore, that IF the p21 worked in humans, and IF you could use viral vectors in humans, then MAYBE you could use viral vectors in the area of a wound to decrease p21 and increase wound healing. BUT. Those are a lot of ifs.
    So more research required.

  • Scicurious says:

    Also, Lucy (awesome name, is that a "Room with a view" reference?!) it wasn't just ears, it was also limbs and cuts, the MRL mice can regenerate parts of lost toes as well as heal cuts without scarring. In addition, just because your ear piercings will close over doesn't mean they HEAL, capillaries don't come back to the area and you will usually have a mark. And the MRL healed some pretty big ear holes.

  • Tony Jeremiah says:

    6) BUT, p21 is a cell cycle regulator and might have significant implications for cancer.

  • Ryan says:

    Interesting. What forms of cancer are we talking about here? Skin, soft tissue sarcoma...are there any else? If caught early enough before they metastasize couldn't they just be excised along with a safe margin of healthy tissue and then the p21 suppression could re-regenerate the excision? Could cancer form after only 1 month of temporary gene suppression (providing it only takes 1 month to regenerate a large wound)? I guess we'll see. Personally if this thing actually works I would take my chances rather than being disfigured like darkman. Also, if this whole skin regeneration thing did actually work, wouldn't that also mean a cure of sorts for baldness (not just male pattern baldness)?
    Scicurious: People have said the mrl mouse can't regenerate skin wounds. Did the paper actually mention that cuts were regenerated in the p21 knockout mouse? Did it say anything about excisional skin wounds?

  • Ryan says:

    After reading this I can't see p21 being down regulated, even locally.
    "This new mouse model combines the human oncogene ras, which is associated with about 30% of human tumours, and a knockout of the p21 gene, which is thought to slow or stop the onset of cancer. The result is a model where 100% of the ras/p21 mice develop tumours by day 63, whereas the mice in the control group with only the ras transgene had only a 22% incidence of tumours in 221 days. This is nearly five times as many mice developing tumours in less than a third of the time."

  • Aly says:

    Wow. Really cool! I have worked with planaria before and their regenerative abilities are amazing. Wow.

  • Greg says:

    I know the researchers were able to regenerate a non healing ear hole, but were they able to regenerate any wounds that would have otherwise scarred (such as a dorsal skin wound)?