Regenerating appendages

[Iasius]

http://www.physorg.com/news187879295.html#top

1 gene lost = 1 limb regained? Scientists demonstrate mammalian regeneration through single gene deletion
March 15, 2010

A quest that began over a decade ago with a chance observation has reached a milestone: the identification of a gene that may regulate regeneration in mammals. The absence of this single gene, called p21, confers a healing potential in mice long thought to have been lost through evolution and reserved for creatures like flatworms, sponges, and some species of salamander. In a report published today in the Proceedings of the National Academy of Sciences, researchers from The Wistar Institute demonstrate that mice that lack the p21 gene gain the ability to regenerate lost or damaged tissue.

Unlike typical mammals, which heal wounds by forming a scar, these mice begin by forming a blastema, a structure associated with rapid cell growth and de-differentiation as seen in amphibians. According to the Wistar researchers, the loss of p21 causes the cells of these mice to behave more like embryonic stem cells than adult mammalian cells, and their findings provide solid evidence to link tissue regeneration to the control of cell division.

"Much like a newt that has lost a limb, these mice will replace missing or damaged tissue with healthy tissue that lacks any sign of scarring," said the project's lead scientist Ellen Heber-Katz, Ph.D., a professor in Wistar's Molecular and Cellular Oncogenesis program. "While we are just beginning to understand the repercussions of these findings, perhaps, one day we'll be able to accelerate healing in humans by temporarily inactivating the p21 gene."

[...]

This sounds like this could lead to some pretty amazing medical science in the (far) future.

I really lack the basics necessary to understand almost everything in there, but here's a link to the article they mention (subscription-only) and the abstract for anyone interested:

link to the article

Lack of p21 expression links cell cycle control and
appendage regeneration in mice

Khamilia Bedelbaeva, Andrew Snyder, Dmitri Gourevitch, Lise Clark, Xiang-Ming Zhang,
John Leferovich, James M. Cheverud, Paul Lieberman, and Ellen Heber-Katz

Abstract

Animals capable of regenerating multiple tissue types, organs, and
appendages after injury are common yet sporadic and include
some sponge, hydra, planarian, and salamander (i.e., newt and
axolotl) species, but notably such regenerative capacity is rare in
mammals. The adult MRL mouse strain is a rare exception to the
rule that mammals do not regenerate appendage tissue. Certain
commonalities, such as blastema formation and basement membrane
breakdown at the wound site, suggest that MRL mice may
share other features with classical regenerators. As reported here,
MRL fibroblast-like cells have a distinct cell-cycle (G2/M accumulation)
phenotype and a heightened basal and wound site DNA
damage/repair response that is also common to classical regenerators
and mammalian embryonic stem cells. Additionally, a neutral
and alkaline comet assay displayed a persistent level of intrinsic
DNA damage in cells derived from the MRL mouse. Similar to
mouse ES cells, the p53-target p21 was not expressed in MRL ear
fibroblasts. Because the p53/p21 axis plays a central role in the
DNA damage response and cell cycle control, we directly tested
the hypothesis that p21 down-regulation could functionally induce
a regenerative response in an appendage of an otherwise nonregenerating
mouse strain. Using the ear hole closure phenotype,
a genetically mapped and reliable quantitative indicator of
regeneration in the MRL mouse, we show that the unrelated
Cdkn1atmi/Tyj/J p21-/- mouse (unlike the B6129SF2/J WT control)
closes ear holes similar to MRL mice, providing a firm link between
cell cycle checkpoint control and tissue regeneration.

 

[Robert Maxwell]

That's really exciting stuff. It sounds like your body doesn't "forget" how to regenerate limbs, nor does it lack the ability, there's just a gene that showed up somewhere along the way that shut off this capability. This makes me wonder if p21 confers some as-yet-unknown evolutionary advantage, since one would think creatures capable of regenerating would survive better than those who can't.

Then again, there is also a significant energy cost in regenerating appendages, and it may be prohibitive for larger mammals. Infection is likely another big factor to make regeneration a hindrance rather than a help. The faster a wound closes up, the less opportunity there is for infection to take root. If you're going to be rebuilding a limb from scratch, you'll be vulnerable for quite a while, I would think.

 

[Iasius]

That's really exciting stuff. It sounds like your body doesn't "forget" how to regenerate limbs, nor does it lack the ability, there's just a gene that showed up somewhere along the way that shut off this capability. This makes me wonder if p21 confers some as-yet-unknown evolutionary advantage, since one would think creatures capable of regenerating would survive better than those who can't.

Then again, there is also a significant energy cost in regenerating appendages, and it may be prohibitive for larger mammals. Infection is likely another big factor to make regeneration a hindrance rather than a help. The faster a wound closes up, the less opportunity there is for infection to take root. If you're going to be rebuilding a limb from scratch, you'll be vulnerable for quite a while, I would think.

Yeah, I've seen two explanations of why the mammalian approach may have evolutionary advantages:
a) Cancer
b) Your point about regeneration possibly taking longer/being more energy intensive.

However, as modern humans, we don't have to worry about b) very much these days, at least in much of the world.

This would be especially great if we could develop the means to somehow temporarily inactivate that gene during convalescence.

Alternatively, it might provide a way towards growing replacement organs.


Maybe one of these days we'll just need a pill and suddenly grow a new kidney.

 

[farmkid]

That's really exciting stuff. It sounds like your body doesn't "forget" how to regenerate limbs, nor does it lack the ability, there's just a gene that showed up somewhere along the way that shut off this capability. This makes me wonder if p21 confers some as-yet-unknown evolutionary advantage, since one would think creatures capable of regenerating would survive better than those who can't.

p21 is a very important protein DNA damage repair. It's been a while since I studied that, but as I remember, p21 stops the cell cycle at a certain point in response to DNA damage to give the cell time to repair the damage. If the cell tries to replicate its DNA or divide before that damage is repaired, the results can be very bad. The most likely result of loss p21 would be a dramatic increase in cancer, especially in response to DNA damaging things such as sunburn or some drugs or radiation.

 

[Robert Maxwell]

Thanks for the explanation, farmkid! That makes a lot of sense. I didn't think about the cancer angle until after I made my post. One would need to monitor regeneration very closely to avoid having it go out of control and become malignant.

 

[Lindley]

Yeah, the last thing you want is your missing pinky turning into John Simm.

 

[sojourner]

How long before someone comes out with a skin cream that has a "p21 inhibitor to reduce lines and the appearance of old scars"?

But yeah, this is a pretty cool find, if they can control the effects to localized usage on the body, it may lead not only to limbs but organs being regenerated. Hair folicals? better healing of broken limbs? lots of possibilities!

 

[Iasius]

p21 is a very important protein DNA damage repair. It's been a while since I studied that, but as I remember, p21 stops the cell cycle at a certain point in response to DNA damage to give the cell time to repair the damage. If the cell tries to replicate its DNA or divide before that damage is repaired, the results can be very bad. The most likely result of loss p21 would be a dramatic increase in cancer, especially in response to DNA damaging things such as sunburn or some drugs or radiation.

This is a possible serious downside, but I wonder about this part of the first article I left out:

"In normal cells, p21 acts like a brake to block cell cycle progression in the event of DNA damage, preventing the cells from dividing and potentially becoming cancerous," Heber-Katz said. "In these mice without p21, we do see the expected increase in DNA damage, but surprisingly no increase in cancer has been reported."

 

[scotpens]

. . . if they can control the effects to localized usage on the body, it may lead not only to limbs but organs being regenerated. Hair folicals? better healing of broken limbs? lots of possibilities!

You realize what this means?

NO BALD STARSHIP CAPTAINS in the 24th Century!