9 replies to this topic

[rillastate]

An exerpt from Kevin's regeneration articles in the Stem Cell Section:

"...It's an evolutionary mystery. The ability to regrow legs and eyes seems like a clear Darwinian advantage - one that surviving generations would have retained. But a paradox of regeneration is that the higher you move up the evolutionary chain, the less likely you'll have the ability to regrow limbs or organs. Keating's mission: figure out the cause of this paradox - and reverse it."


Mark Keating's theory for this paradox:

"Keating's theory is that once we left the swamp and became warm-blooded, our survival priorities changed and scarring became essential, since it kept us from bleeding to death and lowered the chance that we'd develop a fatal infection."


Another mystery:

This is certainly true, but there may be a more fundamental reason our limb restoration program doesn't work anymore: cancer. In order to regenerate, the body has to produce lots of new cells quickly, in a localized area - a process that happens to look a lot like the growth of a tumor. Conceivably, at some point in evolutionary history, it became more important for our body to destroy fast-dividing cells than to preserve them. What this means in terms of restoring our regenerative abilities is harder to determine. Under the circumstances, one might expect animals that regenerate regularly to get cancer more often, but oddly enough the opposite is true: salamanders are one of a very small number of species that don't get cancer at all.



My Question:

When we finally fully figure out why exactly the higher you move up the evolutionary chain, the less likely you have the ability to regrow limbs or organs and how to apply this to humans, is it safe to assume that sometime in the process of figuring out this paradox, we will also most likely learn why Salamanders don't get cancer even though they regenerate via fast dividing cells and then apply this knowledge to humans so that we can somehow one day be able to regenerate AND avoid or turn off getting cancer in humans instead of waiting until we get cancer and then doing something about it?

[kevin]

I think it is very safe to assume so..

The idea of epigenetic reprogramming being essential to dedifferentiation is just beginning to be appreciated as well. There is much work going into this area and we can look to the near future on some breakthroughs in discovering how histone acetylation and methylation govern gene expression.

[John Schloendorn]

I think it is the same sort of mircale that human infants nearly never get cancer, although they come from a germ-line that is billions of years old and regenerates entire bodies all the time. It looks like we'll have to get used to the fact that "perfect" preservation and evolution of our genetic material is possible and the only reason that we age and some amphibians and reptiles don't is that evolution "didn't care" to fix it in us, but "did care" in them.

We have these "perfect" regenerator cells only in the germ-line, while some salamanders appear to have some in their somatic bodies. The rest of the salamander's soma, including his "normal" adult stem cells are constantly turned over, which may be the reason they do not get cancer. There is one thing that seems absolutely critical for the development of cancer in an organism with many cancer defenses: Division time to mutate them all away [1].

Therefore, when we ask if stem cell transplantations from exogenous "perfect" sources can fix aging, the most important thing to look for is how long it takes before cancers can derive from the new cells.

[jwb1234567890]

I think the main factor for why we evolved away our regenerative capability has been due to infectious disease. Infectious disease rate is reduced by the formation of scar tissue as it is a more rapid process than the equivalent regenerative process. Unfortunately once the scar tissue is formed regeneration halts.

If you research spinal cord damage you will see that one of the reasons people don't recover full mobility is precisely because there is scar tissue in the way blocking axonal regrowth.

If you google for MRL mouse you will see an example of a mouse strain which has a low rate of scar tissue formation and regenerates heart and skin tissue. I vaguely recall that the mouse has a shortened lifespan but this may not necessarily have anything to do with its regenerative capability.

I don't think we will get to the point in the near future where we will have the regenerative capability of a salamander, but I do believe we will get to the point where we can transiently express the required proteins to for example repair spinal cord damage or regrow a limb.

[rillastate]

An example of this system of negative regulation is related to muscle growth. There is a gene that encodes a protein called myostatin whose function is to prevent the growth of muscle. But whenever one exercises using resistance training for example, it suppresses myostatin temporarily and one is able to achieve some small increase in muscle growth. In cattle this gene was knocked out and the cattle developed prodigious amounts of muscle with very little body fat and looked like bovine Schwarzneggers. They also had no adverse metabolic effects and were not predisposed to cancer. Why have mammals been selected for this strange regulatory mechanism? Firstly because it appears it is easier to have certain genes always switched on and secondly maintaining so much muscle requires an enormous caloric investment.

It could well be that a regenerative system would require an investment that has been selected against - but it may not mean that like the myostatin system it is otherwise harmful if switched on.

"...prodigious amounts of muscle with very little body fat..." and "...no adverse metabolic effects and were not predisposed to cancer..." and "...requires an enormous caloric investment." [:o]

Well, lets just do away with this protein called myostatin. I can understand why it would have been useful in the past. Fat burns slower than carbohydrates and protein so having excess fats to get you through that winter or famine as a caveman must have been essential, but now in modern times it doesn't do much justice. So why not knock out this gene in humans so we can all look lean and muscular with[EDIT: Replace "with" with "without"] all the draining squats, deadlifts and cleans and be able to take in as much calories as bodybuilders in the off/bulk season without the fat gain?

With "...no adverse metabolic effects..." or predispositions to cancer, it would seem silly to use dangerous steroids and growth hormones to beef up when all you have to do is switch a certain gene. The government would save so much money because they would no longer need to fight steroid and hormone abuses, or pass legislation for sports, or regulate borderline-legal HGH spam in your email, and deal with medical treatments due to long-term steroid and growth hormone abuse.

Plus all those FAKE testosterone and hgh anti-aging marketing tactics would probably be rendered obsolete if all you had to do to get lean, muscular and healthy without dangerous side affects was to get some gene therapy.

I'm very new to this stuff and maybe i'm wrong in thinking it's so easy to just switch a gene on or off, but if they are doing it in cattle as you say, wouldn't they then be able to do this in humans? If so, why isn't this being implemented?


EDIT: Replace "with" with "without"

Edited by rillastate, 15 July 2005 - 08:06 PM.

[John Schloendorn]

Because they can do it only in unborn cattle, at a roughly 200 cell stage. There is even a strain of cattle called the "belgium blue" that has acquired this mutation naturally and continues to propagate it.
But hey, by the time you're ready, gene and cell therapy might well be advanced enough to get the job done. So why don't you go ahead and do it. If you get it to work, i'm sure you'll get a millionaire ;-)

[John Schloendorn]

Sounds like a good idea. I guess one might also have a shot with small molecule pharmaceuticals that bind to the myostatin protein and take it out. One can indeed do incredibly many things in the biotech sector that are not being done simply because no one had the guts to try them yet. These are interesting times.

[apocalypse]

I'd say in non-social organisms it is due to the regen ability cost not being up to snuff in the natural environment.(randomness of food-availability and mortality compromises survival of individuals undergoing regen it's best to spend resources in offspring/etc. There was a recent article-don't recall where- where it was shown that even establishing a perm memory had a cost that could compromise survival-aka as better memorizers died first given a subs env stress in the experiment-. That is simply forming memories what'd be the cost to regen entire limbs? would such energy not be better spent elsewhere? )


In social organisms, specially more advanced ones, should this be possible it may create individuals who're resources hogs and compromise the reproductive success of the local social group as compared to other groups.(ex the chief gets injured and another takes his place vs a chief gets injured and receives extra-nurturing aka energy that could've gone into offspring or other adults.)