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Scientists Demonstrate Mammalian Tissue Regeneration
telomerewhythere writes "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. '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.' Here is the academic paper for those with PNAS access."
We can all be Wolverine now? Cool!
Now I can finally start my restaurant (which specializes in mouse-tail delicacies) without PETA breathing down my neck. "Look: it's growing back!" Mouse-tail soup anyone?
You know this discussion will degenerate into how this can be applied to growing a longer penis.
"No matter where you go, there you are." -- Buckaroo Banzai
What the side effects are. One would(perhaps naively) assume that regeneration is an obvious survival advantage, and that losing regenerative capabilities would be a handicap. That being so, one would tend to suspect that an anti-regeneration gene would be fairly strongly selected against. Since this gene is, in fact, rampant in mammals, one is led to the suspicion that there must be some sort of upside.
Is it something more or less irrelevant to modern humans(at least those wealthy enough to ever be genetically engineered), something like "without any sort of medical care, most serious injuries were fatal before regeneration could occur, so the extra energy costs weren't worth it", or is it some kicker of the "Well, without a whole bunch of other adaptations possessed by certain amphibians and creepy-crawlies, you'll 'regenerate' yourself entirely full of tumors by age 20." flavor?
The next step is to make some p21 specific RNA interference molecules and shut it down in an adult, non-regenerative mouse. Then clip its ear and see what happens.
Since it also increases apoptosis, would this make a good diet pill?
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Well, they claim that they thought it was "lost to evolution"... I assume the fact that the gene is not active today is the result of evolution. So that implies the question Why is it inactive? I would think the ability to regenerate body parts on demand would be an evolutionary advantage, wouldn't it? So something must not work correctly (or there must be some kind of side effect)... It could be as simple as we didn't have enough nutrition at the time to be able to support it, and would die of malnourishment when we'd otherwise live with the injury... But I do agree, it does seem "too easy". They must be a negative here that we haven't figured out... I guess it's time to welcome our new self-healing mouse overlords...
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Macro vs Micro. Regenerating body parts is great. Pretty much freezing genetic diversity with a bunch of near immortal beings? Not so much.
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...in practice, do we have the technology to knock this gene out in humans? That's the key thing. Either you have to engineer every human to have the gene before birth, or you have to do a live fix. And a live fix has all sorts of complications.
Of course, I'm completely ignoring potential side effects. This is best if you imagine a drug for it being advertised: "Regrowitol may cause side effects including cancer, accessory limbs, mutation into evil lizard creature..."
We're living in the future, sure. But we don't have all the cheat codes for reality yet.
A lot of people are asking why evolution has taken away our regenerative capacities, and are guessing what the downside of this regeneration is.
P21 is involved with anti-cancer. It arrests the cell cycle when DNA damage occurs, allowing the damage to be repaired (so mistakes are not carried forward into new generations). Or if the damage is too severe, the cell is made senescent (they lose the ability to reproduce and instead lead out a gentle retirement, performing their normal job until they just die of old age)
P21 knockout mice show a lot of carcinomas and P21 is also up-regulated by and works to remedy excessive oxidative stress. It's very unlikely this research is going to lead to a pill that knocks out P21 and lets us grow limbs back. It will only lead to a greater understanding of how our pathways work.
Not all mutations are good. Some mutations are bad. Sometimes multiple mutations occur at the same time... Maybe another highly beneficial mutation occurred at the same time as this one was lost... Imagine losing a limb... Not as easy to run away from predators while your limb is growing back... May not have been advantageous enough..
Of course the caveat to using mice to judge how a gene affects long-term development of cancer is that there really is no "long-term" on a human scale in mouse studies, since they only live about 3 years at most.
I'm also not entirely familiar with the effect of p21-deficiency in cases where major tumor suppressors are deregulated or otherwise deficient. It is feasible that in the absence of further regulation, the absence of a major cell cycle checkpoint will lead to a more severe phenotype, whether in terms of being more tumor prone, or development of more aggressive tumors.
"I would think the ability to regenerate body parts on demand would be an evolutionary advantage"
What advantage could regeneration provide when survival rates for amputation were abysmal before modern medicine?
Maybe changes in bacteria made regeneration pointless in larger lifeforms (which take longer to heal)?
It's speculation, but I guess the only way we can know if it can be done is to experiment.
I can think of a couple reasons why this feature may have been dropped. nutrition (regrowing something is a hell of a lot more resource intensive than just closing the hole) and infection prevention (just closing the hole is a lot faster than regrowing something, so less chance of it getting infected). Both of these were relevant considerations very recently and evolution is pretty slow.
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Lizards are reptiles.
Not necessarily. A lot of small animals are pretty much disposable: they're sufficiently fragile that there's only a very narrow boundary between a trivial injury and a fatal one. (And anyone who's kept small birds and animals will know that if they're hurt beyond a certain point they'll simply go into shock and die.)
So it's entirely plausible that the gene might have been caused by a spot mutation very early on while all mammals were basically mice, and it then had a sufficiently small effect on actual survivability that the trait didn't get bred out. Later, once the small, disposable animals turned into large, expensive ones, it was too late.
It is interesting that both birds and animals appear to lack this trait, though. We both descend from much the same sort of lizards but in different directions. Finding out exactly where this gene sequence appeared might be productive.
(Of course, I want to know when we'll be able to get gene therapy to suppress the gene. Assuming it works in humans, and that the gene doesn't do anything else critical, it might even be fairly straightforward! But probably won't happen soon and I'm certainly not volunteering to be the guinea pig...)
When you are driving in your car and run over a nail, it's often cheaper to just patch the tire rather than to replace it. You're generally back on the road faster as well.
In case of large animals it may take very long to replace the lost body part. Maybe adaptation is simply faster, and more energy efficient. Same probably for grievous wounds. Or maybe it's just not worth it at all, and the time it took to replace or get over such injury resulted in death of both. But the suppressed gene code was easier to write? Damn lazy programmers...
Sure anyone with even a vague knowledge of evolution and basic highschool genetics will worry, but as long as they make vague promises like bigger dicks, hair regrowth and weight loss pills, they won't have any problems.
Any form of health care is dangerous this way.
Consider this: we can (and do) save many children with birth defects, often we are succesfull enough so that they can leard normal life (and even be oblivious to any issues). Problem is that some of theese defects are hereditary. Guess what? Next generation is worse off as far as ratio of defects is concerned.
We obviously will never do "sparta" thing and kill of children society finds undesirable. Nor will anyone with genetic defect be prevented from having children. Neither is civilized resolution or would be even remotelly popular (would you want to risk your child falling victim to it? noone would.)
Anyway, I would not worry about this particular medical advance. This regeneration propably caused cancer if it got out of controll (cancer with nondiversified cells as medium is quite scarry).
-- Technology for the sake of technology is as pathetic as eschewing technology because it's technology.
This might be true, the bad mutation might even be non fatal but that is not really the point. The thing to consider is the evolutionary advantage (or disadvantage) it gives. I would think that bad mutations give an evolutionary disadvantage and thus be selected against. So the question really is... "What sort of evolutionary advantage does it impart?" I really don't know the answer and I suspect that the researchers are just beginning to answer that question.
I think you have an interesting point here on the resource requirements of regeneration. Part of the obesity problem is that our bodies evolved to store whatever they couldn't use right now for later, so it stands to reason that such things were "turned off" for efficiency's sake. We didn't necessarily evolve in a land of plenty
As for infection rates, I would like to see that study done, too...
Dan
Darwinism is cruel... Nature does things for a reason.
Narture wants to be anthropomorphized ;)
It nature is so cruel and barbaric, then for what reason did it evolve human beings who feel sympathy, empathy, are able to learn, and practice healing arts?
Computers are useless. They can only give you answers.
-- Pablo Picasso
But this still makes me giddy for the future of Medicine.
Nothing lasts forever but the certainty of change.
It is unlikely that a process so complex as mammalian tissue regeneration be controlled by a single gene. Moreover, p21 mutations have been associated with cancers. Which brings forth another question: why is it that only "lower" organisms (and mammalian fetuses) are capable of scar-less tissue regeneration? The answer is yet to be discovered but it is very likely that evolution had to stroke a balance between cancer control and tissue regeneration. It won't be easy to figure out "the way back" to regeneration, or even to avoid the risks of such a path.
Ummm, the ability to regenerate lost body parts doesn't make you immortal. It just makes it less likely that the loss of an arm or a leg will end your life.
And it is easy to run away without a limb at all?
If simply switching off the one gene is enough to allow regeneration, then it WOULD happen with an incidence similar to other single base pair change genetic defects. Something else is going on here. It could be that larger animals with the gene turned off die in the womb or something.
Part of the obesity problem ...
So this gene will be a solution to that problem as well:
You're fat? No problem, just lop off a leg, it'll regrow, and in the process consume the excess belly...
Well, they claim that they thought it was "lost to evolution"... I assume the fact that the gene is not active today is the result of evolution. So that implies the question Why is it inactive? I would think the ability to regenerate body parts on demand would be an evolutionary advantage, wouldn't it?.
Supposedly around 8% of human DNA was inserted by viruses into our genome. It could be that a virus in the past messed up our ancestor badly enough to lose regeneration and killed of all the rest. Also evolution doesn't have a "goal" our non-regenerative ancestor was just lucky that through some trait it was the best adapted to the environment at the time and it survived. It doesn't mean regeneration had a negative side to it.
If all else fails, immortality can always be assured by spectacular error.
Here is the academic paper for those with PNAS access.
I have access to a PNAS. Sometimes I let my wife have access to it, too.
The wikipedia entry for p21 (http://en.wikipedia.org/wiki/P21) is somewhat misleading about its relationship with cancer. For a good review, see: http://journals.cambridge.org/action/displayFulltext?type=1&fid=1919868&jid=ERM&volumeId=10&issueId=-1&aid=1919860 Excerpt: "However, p21-null mice were found to be more susceptible to chemically induced tumours of the skin (Ref. 94) and colon (Ref. 95), and following irradiation they displayed increased tumourigenesis and metastases (Ref. 96). In addition, using different mouse strains, others have found that p21-null mice exhibit spontaneous tumour formation in the background of other genetic knockouts, such as Muc22/2 (lacking mucin 2) (Ref. 97) and Apc1638/2 (carrying a mutant allele of the adenomatosis polyposis coli gene) (Ref. 98). Furthermore, subsequent to the initial description of p21-null mice, investigators have found that p21-null mice bred on a 129Sv/ C57BL6 50:50 background did in fact develop spontaneous tumours at an average age of 16 months (Ref. 99). Collectively, these mouse studies demonstrated the importance of p21 in mediating the G1 checkpoint, and its ability to function as a tumour suppressor."
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What medical care do newts have access to?
It's incredibly funny to watch all the well-fed deep thinkers here scratch their heads and try to come up with complicated solutions to a trivial problem: cold blooded animals don't have to keep eating on a daily basis to survive. Ergo, they have time to regenerate. They can just find a place to curl up while it happens.
Warm blooded animals need a much more regular food supply. Ergo, there is an advantage to them in a fast and adequate healing.
No mysterious cancer-causing whatevers need be invoked. It is most probably a simple issue of energy budget.
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Or perhaps most common injury is just a small scratch, not losing your limb. Even the result looks nasty, faster healing offers one very important benefit. Open wounds tend to infect and that can cause serious illness or even death without modern medicine. It is not hard to imagine that healing your wounds a day or two faster would decrease the chance of getting sick a big time.
Presumably in the past there must have been some evolutionary advantage to developing scars rather than regrowing a new limb.
Speed is one possible reason. Another may be that a lot of scars are caused by things that persist (e.g. splinters, fibers, parasites), and it is potentially useful to encapsulate them in fibrous tissue, rather than regenerating normal tissue.
As you demonstrate you already know, cancer prevention is partly about restricting the uncontrolled growth of cells; a tumor is cells growing without controls, so many natural defenses against cancer place controls on cell growth, sometimes by inhibiting healthy cell growth as well.
Turning off a gene like p21 is probably going to impact your body's ability to control and respond to cancer:
http://www.google.com/search?q=p21+cancer
In particular, in that search is a powerpoint presentation discussing the body's immunoresponse to cancer, in which p53 initiates and governs several important responses, one of which involves turning on p21 to begin replacing it with healthy cells.
Obviously, that observed response goes away if you knock out p21; it's likely that without the aid of that process, the process is impacted and cancer is more likely to succeed.
There are numerous other examples of p21 aiding cancer prevention, removal, and replacement in that search - have a look.
I'd like to see the comparative cancer rates of normal mice and p21-knockout mice.