Regeneration as Controlled Cancer

Parallels can be drawn and biochemical similarities pointed out between (a) limb and organ regeneration in lower animals like newts and salamanders, (b) embryonic growth in all species, and (c) cancer. Regeneration of lost limbs is a controlled replication of the processes of embryonic development, while cancer stems from those same processes unleashed and run wild. Nothing is quite as simple as that, of course, but it is a framework for thinking about how these fields of life science research overlap and inform one another.

This is well illustrated by a recent advance from one of the research groups studying newt biochemistry with an eye to replicating it in mammals - or at least understanding the crucial differences. We should not be surprised to see that cancer-suppressing genes are at the heart of the puzzle:

Although there's been a lot of discussion about using adult or embryonic stem cells to repair or revitalize tissues throughout the body, in this case the researchers weren't studying stem cells. Instead they were investigating whether myocytes, run-of-the mill muscle cells that normally don't divide, can be induced to re-enter the cell cycle and begin proliferating. This is important because most specialized, or differentiated, cells in mammals are locked into a steady state that does not allow cell division. And without cell division, it is not possible to get regeneration. In contrast, the cells of some types of amphibians are able to replace lost or damaged tissue by entering the cell cycle to give rise to more muscle cells. While doing so, the cells maintain their muscle identity, which prevents them from straying from the beaten path and becoming other, less useful cell types.

Previous research had shown that a tumor suppressor called retinoblastoma, or Rb, plays an important role in preventing many types of specialized mammalian cells, including those found in muscle, from dividing willy-nilly. But the effect of blocking the expression of Rb in mammalian cells has been inconsistent: In some cases it has allowed the cells to hop back into the cell cycle; in others, it hasn't. The researchers employed some evolutionary detective work to figure out that another tumor suppressor called ARF might be involved. Like Rb, ARF works to throw the brakes on the cell cycle in response to internal signals. An examination of the evolutionary tree provided a key clue. They saw that ARF first arose in chickens. It is found in other birds and mammals, but not in animals like salamanders nestled on the lower branches. Tellingly, it's also missing in cell lines that begin cycling when Rb is lost, and it is expressed at lower-than-normal levels in mammalian livers - the only organ that we humans can regenerate.

Based on previous investigators' work with newts, Blau said it "seemed to us that they don't have the same limitations on growth. We hypothesized that maybe, during evolution, humans gained a tumor suppressor not present in lower animals at the expense of regeneration."

Sure enough, Pajcini and Pomerantz found that blocking the expression of both Rb and ARF allowed individual myocytes isolated from mouse muscle to dedifferentiate and begin dividing. When they put the cells back into the mice, they were able to merge with existing muscle fibers - as long as Rb expression was restored. Without Rb the transplanted cells proliferated excessively and disrupted the structure of the original muscle.

This is a modest step towards being able to carefully spur regeneration in mice; one might envisage researchers switching gene expression of Rb and ARF on and off in tissues during the regenerative process so as to obtain the desired result of controlled regrowth while avoiding cancer. But I can't imagine that will be a straightforward process.

On this topic you might recall that at least one breed of laboratory mouse - the MRL breed - is in fact able to regenerate unusually well for a mammal, and earlier this year that capability was pinned down to removal of the p21 gene:

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.

Surprise, surprise, another connection to cell division and cancer suppression. So far it looks like making mammals regenerate like amphibians is a realistic undertaking for modern medicine, but will require great care in its implementation so as to avoid the risk of cancer.

Comments

Could you do me a big favor? I know you don't know me, but we both share the common interest of increasing human well being.

If you only had 20 minutes, what would you do to convince an intelligent (college educated or professional) audience of the significance of life extension beyond 120 years? Assume they do not commit the tithonus error and are rational enough to understand that probably do want to live indefinitely so long as the quality of life meets their own standard. The problem then becomes convincing others that it is indeed possible to live very very long lives.

However, how can you convince someone that extreme life extension is scientificially valid research? It seems like some persons will dismiss the possibility because their is no such empirical example, just as planets outside our solar system were not outright denied, but ignored.

I realize your blogposts cover a large swath of what I have asked but consider the presuppositional distinction in those who disaggree may present itself as a strong need for empirical evidence combined with notions of humility that frankly do not fit in with my worldview.

I have a few ideas that will be helpful but are not very original. Which may be a strength given the usual distaste for counterintuitive ideas even among those who some may classify as thoughtful. These include teaching rational values (not logic per se, but heuristics that vastly improve the ability to think coherantly) combined with a culture that fosters a lust for life. Why wait for 10,000 year lives to start learning how to enjoy life now?

It is the latter idea that is entirely missing from your blog. You don't mention what it is we are supposed to do with indefinte lives, yet this is a primary reason why less thoughtful individuals believe in the tithonos error because they have few trustworthy sources for eudamonia.

Now, I know why most skeptics/humanists/atheists/rationalists type folks don't advocate being an authority on what to do with ones life. Considering the fact that most folks are not involved with life extension (or other projects related to human flourishing on a long time scale) it seems their is a desperate need for greater rationality even among the so called 'rational' and greater cooperation. The latter must be based on something other than stoic belief in self reliance.

That being said, I do like your blog and realize it doesn't address teleology and rationality (and perhaps shouldn't) but it seems that this isn't a as succesful a strategy in my view than engagement with these issues. I do realize blogging is a lot of work, etc, etc, so this isn't chastisement but a suggestion and a question given your semi-expertise compared to my layman's interest in the topic of SENS.

Posted by: Matthew at August 6th, 2010 8:02 AM

Superb snippet I have been on top of the research and this was dead on and I share the same exact perspective on regeneration explained in the first paragraph. Glad to know I'm not the only one who can see this mess clearly.

@Matthew why are u ranting here? It's not the place and your off topic, I think u need to engage with ur own issues. Seems like ur more interested in life extension for negative personal reasons than to enjoy life. I mean after all that effort to write that do u really think ur gonna get a response or have a constructive debate on a blogs comment section? Start ur own blog ranting ur issues otherwise ur wasting urs and everyone else's time.

Posted by: eddie at December 23rd, 2010 2:37 PM

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