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 , 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 than adult , and their findings provide solid evidence to link 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."

Heber-Katz and her colleagues used a p21 knockout mouse to help solve a mystery first encountered in 1996 regarding another mouse strain in her laboratory. MRL mice, which were being tested in an autoimmunity experiment, had holes pierced in their ears to create a commonly used life-long identification marker. A few weeks later, investigators discovered that the earholes had closed without a trace. While the experiment was ruined, it left the researchers with a new question: Was the MRL mouse a window into mammalian regeneration?

The discovery set the Heber-Katz laboratory off on two parallel paths. Working with geneticists Elizabeth Blankenhorn, Ph.D., at Drexel University, and James Cheverud, Ph.D., at Washington University, the laboratory focused on mapping the critical genes that turn MRL mice into healers. Meanwhile, cellular studies ongoing at Wistar revealed that MRL cells behaved very differently than cells from "non-healer" mouse strains in culture. Khamilia Bedebaeva, M.D., Ph.D., having studied genetic effects following the Chernobyl reactor radiation accident, noticed immediately that these cells were atypical, showing profound differences in cell cycle characteristics and DNA damage. This led Andrew Snyder, Ph.D., to explore the DNA damage pathway and its effects on cell cycle control.

Snyder found that p21, a cell cycle regulator, was consistently inactive in cells from the MRL mouse ear. P21 expression is tightly controlled by the tumor suppressor p53, another regulator of cell division and a known factor in many forms of cancer. The ultimate experiment was to show that a mouse lacking p21 would demonstrate a regenerative response similar to that seen in the MRL mouse. And this indeed was the case. As it turned out, p21 knockout mice had already been created, were readily available, and widely used in many studies. What had not been noted was that these mice could heal their ears.

"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."

In fact, the researchers saw an increase in apoptosis in MRL mice - also known as programmed cell death - the cell's self-destruct mechanism that is often switched on when DNA has been damaged. According to Heber-Katz, this is exactly the sort of behavior seen in naturally regenerative creatures.

"The combined effects of an increase in highly regenerative cells and apoptosis may allow the cells of these organisms to divide rapidly without going out of control and becoming cancerous," Heber-Katz said. "In fact, it is similar to what is seen in mammalian embryos, where p21 also happens to be inactive after DNA damage. The down regulation of p21 promotes the induced pluripotent state in mammalian cells, highlighting a correlation between stem , tissue regeneration, and the cell cycle."


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47 comments

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in7x
5 / 5 (2) Mar 15, 2010
Curious why evolution would prefer scarring over regeneration.

I guess the system became so complicated that, as mentioned, that regenerating organism suffered such catastrophic DNA damage or cancer growth that they were wiped out before they could reproduce... Let alone nightmare scenarios:

http://www.scific...tsuo.jpg

:p
gunslingor1
1.7 / 5 (3) Mar 15, 2010
I agree, mammals are far to complicated to have a limb rebuilt from scratch using 1 gene. Chances are, you'd need the entire thing and cancer is highly likely. Keep going though guys, never know what you'll find out.
Caliban
3 / 5 (8) Mar 15, 2010
Maybe, or maybe this gene arose as a mechanism to ensure that individuals would eventually "wear out", as a population control mechanism.
andrzej_w_lipski
4.5 / 5 (2) Mar 15, 2010
I wonder if there is a cost for this rapid cell generation. It may require a lot of energy, expenditure of heat to maintain that kind of trait and natural selection favored the energy efficient species through the ice ages.
trekgeek1
3.7 / 5 (3) Mar 15, 2010
I agree with the "wear out" theory. If you are nearly indestructible, your population grows too quickly and resources dwindle. It seems that if you can regenerate, you don't pay as heavy a penalty for genetic deficiencies. It seems that making an individual weaker makes a species stronger by accelerating natural selection. If you have a muscle disorder and a predator rips your leg off and it grows back, you might reproduce and spread your muscle disorder. If you don't regenerate, you die.
NeilFarbstein
3 / 5 (4) Mar 15, 2010
I wonder if there is a cost for this rapid cell generation. It may require a lot of energy, expenditure of heat to maintain that kind of trait and natural selection favored the energy efficient species through the ice ages.


I'm wondering also. p21 might be the first gene discovered that confers the regeneration trait in animals lacking it. There might be others. The monetary cost of achieving regeneration in humans might be less than thought. There are a lot of anecdotal stories about people that lost part of a limb that later regenerated. I'm involved in silencer RNA research and silencing the p21 gene might be a path to regenerating human tissues. Three years ago in 2006 and 2007 my company was doing contract research on silencer RNA production on a large scale.
Contact me at protn7@att.net if you are interested in researching it.
poi
2 / 5 (3) Mar 15, 2010
In fact, the researchers saw an increase in apoptosis in MRL mice - also known as programmed cell death - the cell's self-destruct mechanism that is often switched on when DNA has been damaged. According to Heber-Katz, this is exactly the sort of behavior seen in naturally regenerative creatures.

Can't wait to see falling crippled limbs, or molting kids, as an everyday affair. May be bad for cosmetics business though. They will most probably tweek down this tech and come out as a 6 month guaranteed youthfulness, or something.
fixer
4 / 5 (1) Mar 15, 2010
This looks like one of those developments that has truly useful potential.
I remember articles only a few months ago stating this may be possible "in a few years".
Let's keep an eye on this one as it may be the most important medical development in 50 years if it can be applied to humans.
MatthiasF
2 / 5 (2) Mar 15, 2010
I agree, mammals are far to complicated to have a limb rebuilt from scratch using 1 gene. Chances are, you'd need the entire thing and cancer is highly likely. Keep going though guys, never know what you'll find out.


I agree. The gene probably worked itself off after it caused more complicated animals higher cancer rates or shorter lifespans.
Caliban
2 / 5 (3) Mar 15, 2010
In terms of energetic cost- for a human to regenerate say, a leg- You would have to eat like a horse to stay ahead of it- unless of course you could afford to lie down for six months, while your body's efficiency dictated at what rate your food was converted into materiel fo regenerating the limb. Still would be better than lost leg, though.

Looks like we've identified two likely reasons for this gene to be suppressing regen in humans.
ryan_gillis2
4.5 / 5 (2) Mar 15, 2010
Maybe, or maybe this gene arose as a mechanism to ensure that individuals would eventually "wear out", as a population control mechanism.

This is an interesting idea but I would think if it was that simple then a noteworthy increase in longevity of fertility would have been observed in the p21 knockout mice that were already in use for other experiments.
malapropism
4 / 5 (1) Mar 15, 2010
I agree, mammals are far to complicated to have a limb rebuilt from scratch using 1 gene. Chances are, you'd need the entire thing and cancer is highly likely. Keep going though guys, never know what you'll find out.


I agree. The gene probably worked itself off after it caused more complicated animals higher cancer rates or shorter lifespans.

I think you've mistaken the impact of this gene. From what I gather from reading just this article (i.e not the original research papers), the p21 gene acts as a suppressor for regeneration; that is, there is no suggestion here that it somehow encodes for the regeneration of a complex body part like a limb. This would be already encoded by parts of the rest of the genetic make-up of the individual, and enabled within (presumably) stem cells by the inactivation of p21.

Neil Farbstein's suggestion of using gene silencing on p21 is a very interesting and pertinent point, and an idea that is potentially within current technology.
GaryB
3.3 / 5 (7) Mar 15, 2010
I agree with the "wear out" theory. If you are nearly indestructible, your population grows too quickly and resources dwindle. It seems that if you can regenerate, you don't pay as heavy a penalty for genetic deficiencies.


Yous guys is smokin too much theory weed -- just sort of make up what evolution is to fit some half understood facts. You's is all supposing that there's some giant group selection going on -- generations of proto-mice who all died out because they where so successful they caused a habitat collapse. That's some heavy weed dudes.

Basically, evolution reflects how well an individual makes it until they can mate and pop-pups. My, much simpler, guess is that: losing a limb is pretty rare, cancer is not. So we lost regeneration as a trade for lowering the chance of cancer in our youth.
NMSU96
3 / 5 (1) Mar 15, 2010
I have read that children under a certin age have the ability to regrow finger digets that have been cut off in accidents. It would be of interest to know if P21 is turned on or off in these children. It would be usefull to know if p21 type regrowth is only for lims and soft tissue or will repair damaged nervs with out the scar tissue damage.
Trim
2.5 / 5 (2) Mar 16, 2010
Could it be used to grow a new spinal cord? Or a new heart if you were on a heart lung machine? How about curing dementia by removing parts of the damaged brain?
Artistguy
3 / 5 (1) Mar 16, 2010
What if P21 is the genetic equivalent of a completion flag, and deactivating it says to the body "Something's not done or is still in need of work"?
El_Nose
2.5 / 5 (2) Mar 16, 2010
I don't think you would use it to grow a new spinal cord -- but with spinal injusry it is the scar tissue that destroys the ability to walk -- i believe - please correct if i am wrong

and p21 - seems to negate the creation of scar tissue.
DozerIAm
4 / 5 (1) Mar 16, 2010
The removal of p21 seems to negate the creation of scar tissue but does it fix scar tissue is my question... and I believe the answer is no, it acts at the time the damage would normally scar up, so if you deactivated the gene on someone already "healed" they wouldn't regrow a leg where there is now a stump. However for trauma care this might have a near miraculous effect (especially if you could add p21 back in after you've regrown what ever you damaged so you don't start growing cancers or gills or develop a fondness for flies).

As for evolutionary theories, I'm going with trekgeek as far as "It seems that if you can regenerate, you don't pay as heavy a penalty for genetic deficiencies. It seems that making an individual weaker makes a species stronger by accelerating natural selection." However, I disagree with the "population explosion" explanation - I would prefer this to be strictly a "Darwinian model" and / or "energy in - energy out" theory.
NeilFarbstein
1.8 / 5 (4) Mar 16, 2010
You can work split shifts and eat like a monster at night and sleep half the day.
Danny_Bannister
2.5 / 5 (2) Mar 16, 2010
Caliban makes a good point. The amount of energy required to regenerate is enormous and very few societies until recently could support an individual while they grew a new arm or leg. I believe natural selection would make these individuals susceptible to malnutrition and weaker while they recovered from injury. It would favor the ones that were back on there feet (or foot as it were) the quickest. And since natural selection is mainly concerned with the survival of a species it wouldn't matter if a few individuals were lost because the damage was too much to patch.
CouchP
4 / 5 (1) Mar 16, 2010
With the Genes suppressed, would old scars or other types of "traditionally healed" wounds regenerate the missing tissue?
DozerIAm
3 / 5 (1) Mar 16, 2010
With the Genes suppressed, would old scars or other types of "traditionally healed" wounds regenerate the missing tissue?


Experiments will tell (if they ever get that far), but my guess as I said above is "I doubt it". The same mechanism that says "damage, time to scab/clot/scar" will instead say "damage, time to regenerate". But scar tissue is technically damage in the present tense, its "healed over" and I doubt anything would happen.

I'll be happy to be wrong though.

All this said, identifying a gene is pretty darned far from from doing experiments even on lower order mammals, and gettign to human trials may never happen due to the risks of turning the gene off in the first place. Its all nice thought experiments probably for my lifetime.
Giya
4 / 5 (3) Mar 16, 2010
Remember, evolution does not always choose traits that confer an advantage to the organism. Random traits, sometimes even less desirable traits, can proliferate. Perhaps a genetic bottleneck eliminated individuals with the ability to regenerate. It could be a mistake!
Nigel_Bouvart
3 / 5 (1) Mar 16, 2010
I agree with the "wear out" theory. If you are nearly indestructible, your population grows too quickly and resources dwindle. It seems that if you can regenerate, you don't pay as heavy a penalty for genetic deficiencies. It seems that making an individual weaker makes a species stronger by accelerating natural selection. If you have a muscle disorder and a predator rips your leg off and it grows back, you might reproduce and spread your muscle disorder. If you don't regenerate, you die.


So you think a widespread gene arose from a situation that would make its bearer die? How do you suppose this gene propagates itself?
Tiak
2 / 5 (1) Mar 16, 2010
@Giya

A bottleneck at least 100 million years ago, leading to a single disadvantageous gene being proliferated, that just happened to stick around those 100 million years by chance?... Ridiculously unlikely.

Optimistically, the main drawback would be energy usage, where evolutionarily the problem was that the ability would've required twice the amount of food or the like, which would've been unsustainable.

More realistically, it seems pretty likely to shorten lifespans by causing an increased rate of aging.

@the "wear out" theory people

Yeah, just the opposite seems most likely to me. Senescence is caused largely by increased genetic errors, this seems to increase genetic errors, as well as more cell division which itself increases the rate of accumulation of errors.
opticbit
3 / 5 (1) Mar 16, 2010
I saw somewhere that natural selection didn't give mammals the ability to regenerate because they were able to cope with the lost limb, with higher intelligence. Can't wait for human trials, so we can fix what evolution failed to give us. Would be nice for pets too.
dan42day
2.5 / 5 (2) Mar 17, 2010
It might be possible to re-activate a healed wound site after p21 suppression by surgically removing the scar tissue.

The energy argument, while perhaps being a valid reason why limb regeneration would be futile for an injured animal without access to care and feeding assistance, probably doesn't fully explain why this ability was lost.

A slight increase in overall cancer rates however, would.
I'll bet a lot of amputees coming back from Iraq and Afghanistan would gladly accept an increased risk of cancer for their arms and/or legs back. DARPA should pile some money on this.
xlsior
2.7 / 5 (3) Mar 17, 2010
Knowing humanity as I do, I'm inclined to look at the big picture. I predict that this technique will be used, as usual, first to succor troops in battle; once it has been refined, it will become solely available to the elites, who, by that time, will have fully consolidated their political and economic power (how many more "bailouts" should THAT take??) and, thus, be the only ones who can afford it. An old and rather entertaining film, "Zardoz" touches on this. For entertainment purposes only, of course...
Caliban
2 / 5 (3) Mar 17, 2010
How long until the first "regeneration pod" is unveiled?
dev2000
2.7 / 5 (3) Mar 17, 2010
More intelligent animals are less likely to lose body parts. Intelligence is favored by natural selection over regeneration. Nothing mysterious here.

The only twist here is that intelligence has now gotten to the point where regeneration can be regained, overcoming natural selection. Now that's groundbreaking.
fixer
4 / 5 (1) Mar 17, 2010
I doubt that this therapy will be available to just the "elite".
People like us spread the news and you just can't keep a secret these days.
Once the medication to alter the gene is produced it will be registered and copied all over the world.
Mass production = low price.
Caliban
1.7 / 5 (3) Mar 17, 2010
@fixer,
That is, unless, of course, you live in the US, and you are buying some consumer product from SE Asia, or Mexico.
fixer
3 / 5 (1) Mar 17, 2010
True, there is always reason to be suspicious of Asian products, Melamine dust in baby formula comes to mind...
If you stay with mainstream suppliers you should be reasonably safe.
Many major pharma companies deal out of Asia.
Let's get the product up and running first!
Hobbsm51
2.7 / 5 (3) Mar 19, 2010
This initial study says, "In these mice without p21, we do see the expected increase in DNA damage, but surprisingly no increase in cancer has been reported."

So I doubt increase in instances of cancer had anything to do with the selection for/against this gene. Cancer rates would have been substantially lower 100 million years ago because of the lack of man made pollution.

Furthermore, with out the aid of modern medicine, the loss of a limb would have been fatal. Mammals bleed out too quickly. Scaring probably clots wounds quicker and allowing more individuals to survive and reproduce.
bclark76
4 / 5 (1) Mar 19, 2010

Basically, evolution reflects how well an individual makes it until they can mate and pop-pups. My, much simpler, guess is that: losing a limb is pretty rare, cancer is not. So we lost regeneration as a trade for lowering the chance of cancer in our youth.


Yeah, if you are 'in the wild' hopping around with three legs, you probably are going to be eaten or fail to eat long enough that you aren't going to be regenerating, instead you'll be dying. Unless you are a cold blooded amphibian with tiny caloric needs hiding under some leaves in a stream, opportunistically eating any passing flies.
labtvonline
2 / 5 (1) Mar 19, 2010
Wow! This is an absolutely amazing breakthrough! There are so many reasons why this may have become not desirable to evolution for mammals its making my head spin. I wonder if it possibly had anything to do with energy consumption that scar tissue needs less energy that a full limb needs to regenerate? I work for a non-profit that provides science educational videos for students. We have one directly about his process, if you have a sec check it out!
http://www.ndep.u...Building Body Parts
NeilFarbstein
1 / 5 (2) Mar 19, 2010
I doubt it has prospects for penis enlargement.
p21 is a tumor supressor. After you turn off
the suppression the growth might get out of control.
panda
not rated yet Mar 19, 2010
In the actual paper, the authors note that suppression of p21 did NOT allow regeneration of digits (I forget if they were toes or fingers). And yes, they did try to do it. It didn't work.
Erog
not rated yet Mar 21, 2010
"I agree, mammals are far to complicated to have a limb rebuilt from scratch using 1 gene"
Why are people thinking this? did you read? the gene in question is a gene that represses another area . . it is not instructions but a switch.
NeilFarbstein
1 / 5 (2) Mar 21, 2010
This switch controls dozens or hundreds of genes. On master switch might make a big difference. two or three switches working together might regenerate a limb.
panda
not rated yet Mar 21, 2010
Friends, there was NO limb regeneration! The researchers tried but failed with digit regeneration, much less an entire limb. Read the paper.
NeilFarbstein
1 / 5 (2) Mar 21, 2010
They obtained ear lobe regeneration. The article above doesn't discuss their failed limb regeneration experiments. More hype to disappoint the longevity people. Someitme I feel theres hopt that I might grow younger as i age in the future.
DozerIAm
not rated yet Mar 22, 2010
An old and rather entertaining film, "Zardoz" touches on this. For entertainment purposes only, of course...


Sean Connery wearing a girl's bikini bottom and go-go boots, running around witha fu manchu? sorry, that's beyond satire and well into farce! (however, it is good for MST2000 style watching)
foxcopy
not rated yet Mar 27, 2010
My Uncle 55 years old had a motorbike accident and lost half of His left hand pinkie finger, 8 weeks later his finger grew back including the finger nail
I wise quite surprised to see that..
theeradicator
not rated yet Apr 09, 2010
At first I was extremely excited when I read this article - it makes you think humans may finally be able to heal without scars (and we really should be able to by now, scarless fetal wound healing was discovered almost 30 years ago), but what it fails to mention is that the mrl mouse can not regenerate skin wounds - they form scar tissue just like humans. Inhibiting p21 will not allow humans to regenerate skin, cartilage maybe, but not skin. 15 years ago the researches should have done more than punch ear holes, they should have created excisional skin wounds. What a huge disappointment.

https://www.resea...ith_scar

http://www.ecmjou...2a38.pdf
theeradicator
not rated yet Apr 09, 2010
Maybe I'm wrong. Maybe the ear cells of the mrl mouse don't express p21, but the skin wounds did - if that is even possible. I wonder if the p21 knockout mice could regenerate skin wounds or only ear holes.
DozerIAm
not rated yet Apr 12, 2010
My Uncle 55 years old had a motorbike accident and lost half of His left hand pinkie finger, 8 weeks later his finger grew back including the finger nail
I wise quite surprised to see that..

No one is going to call "shenanigans" on this besides me?

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