65 replies to this topic

[jaydfox]

Has anyone given Stem Cells cancer?

Umm, "Mother Nature"? Does "she" qualify as "anyone"?

[Lazarus Long]

I found this topic thread, which so parallels this conversation that I may in the future merge it with this one. For now please review it as well.

Evolution is the cause of aging:
http://www.imminst.o...t=0

And Jay I am uncertain if Stem Cells become directly malignant *naturally* though perhaps the source of stem cells is mutated and the resulting product are the cells that initiate the expressed malignancy. Would you please elaborate?

However I did mean *artificially induced* for the record and I should have been even more specific as I was referring to ESC not ASC.

[jaydfox]

...and I should have been even more specific as I was referring to ESC not ASC.

Ahh! I was referring to ASC, not ESC, and to my limited knowledge, ASC are susceptible to cancer formation, and this susceptability increases with age, due to senescence. I don't know whether ASC are more resistant to becoming cancerous than the typical cell. I would assume so, since their telomerase is upregulated to begin with, so from a cancer formation standpoint, they would be a liability if not better protected than the typical somatic cell against becoming cancerous (i.e., they have one less mutation to undergo before becoming a malignancy, so better protection against the other characteristics of cancer would be a good thing, and hopefully Evolution "agreed". I know I opened myself up to comments from LL on that one, but I couldn't resist ) ).

Jay Fox

[Lazarus Long]

Prometheus:
LL, if you have the facility (and inclination) to merge these threads it would not be a bad idea to create distillations of of key ideas in an executive summary form and place it in a way so that new viewers can very rapidly absorb the essence without getting bogged down in tedium. it would be a terrific contribution to ImmInst.

I do and will, eventually. Consider my prior post a warning of intent but I am still awaiting some reply from the originator of the thread. There is no rush and there are some aspects of a merger that I want to ensure are correct.

One problem with our software is that it will put all posts in chronological order automatically and this means at times in past attempts that we have had confusion generated from breaking up the continuity of discussion. In this case I do not think it is a significant factor but it will place all the earlier posts ahead of those in this thread.

Prometheus:
"BTW a stem cell can become transformed just like any other cell. I am unaware (haven't yet looked) of studies that compare the rate of transformation between ESC's, ASC's, somatic non-senescent and somatic senescent (rather easy to do - just culture each type, expose to mutagen and screen for transformants). "

Jaydfox:
"I don't know whether ASC are more resistant to becoming cancerous than the typical cell. I would assume so, since their telomerase is upregulated to begin with, so from a cancer formation standpoint, they would be a liability if not better protected than the typical somatic cell against becoming cancerous (i.e., they have one less mutation to undergo before becoming a malignancy, so better protection against the other characteristics of cancer would be a good thing, and hopefully Evolution "agreed". I know I opened myself up to comments from LL on that one, but I couldn't resist  ). "

Well actually Jay (and Prometheus) I am aware of tumor growths on developing fetuses en utero. Stem cells do not necessarily provide immunity and if they did this would be something we certainly need to know, and more importantly *why* they would.

Your assumption Jay

I don't know whether ASC are more resistant to becoming cancerous than the typical cell. I would assume so,

is a classic example of the reason scientists don't *assume*, they experiment (testing their assumptions ) ).

I am unaware of this being posed as a specific comparative study on the *resilience and resistance* capacity for ESC versus ASC to become malignant tissue. I think the results would be highly informative.

Actually another separate point of contention is whether the Stem Cells are becoming malignant themselves or being used as the vector to *cause* malignancy?

This again is no small matter and in many respects let me suggest that stem cells and cancerous ones actually share many characteristics in common but two major and obviously important differences are the aspects of *regulated reproduction* and *type specific differentiation* (as defined by the host's DNA).

If cancer cells could be *regulated* and the result produced immortalized viable tissues, which fulfilled the metabolic demands of the host we wouldn't be considering cancer a disease but instead a blessing.

The object of my question is a little more subtle. Let me rephrase it perhaps: Are the Stem Cells *malignant* or are they becoming the vector of malignancy because the *source of the stem cell production* has been mutated to produce malformed stem cells?

We can return to the evolutionary debate in time )

BTW everyone I want to include another topic thread that is a relevant cross reference to this discussion with respect to evolution.
Abiogenesis, DNA, RNA, and Protein Interaction

[Lazarus Long]

Well since you suggest it Jay; back to *Evolutionary Selection* issues.

I am attempting to unify genetic and evolutionary theory into a single structural paradigm that I also suspect will influence how we think about disease. I am not alone in this as thankfully far more studied minds than mine are focused on this same idea.

Let me state a more precise relationship of the logical aspects that I have introduced to now.

1. Selection is the result of each *self aware* programed DNA's *desire* to continue in existence (live) regardless of the form it organizes into and that this is a primary *motive* for all behavioral choice, to include but not presume, an altruistic principle.

2. This drive to continue the existence of the *self aware encrypted DNA form*(an Immortality Instinct, like Schopenhauer's Will to Live or Darwin's Survival Instinct) in each living expression of DNA accomplishes this by the use of two strategies, Reproduction and *Sustaining*. Reproduction drives speciation and Sustaining is a part of the acquisition and defense experience for survival in any specific individual type.

This is the result of the relational aspect to individual environmental choice. Consider it the core binary aspect of Biology but I should warn all that the applied digital dialect of choice is not restricted to the more simplistic yes/no of the number-line but is more a question of, and quest for the Socratic Alternative, a fuzzier form of creative logic.

3. There are divisions of these two base strategies for continuance (Procreation and Defense) into key models related in complexity by asexual/sexual molecular reproduction methodology that reflects a more primal cellular choice of meiotic/mitotic division for procreation and the efficiency of consumption for sustenance versus defense of the region for its acquisition. This suggests that death is not an inherent part of the genetic code but that like a *predator nature* can be programed in.

Defense includes the drive to organize socially in group models to meet a *shared demand for Vigilance and Support* and this results in herd/pack/colonies/hives/cultures and now industries. The idea is predicated in all cases with self awareness and the continuance of self, usually the focus is on streamlining acquisition and then the successful models come into *intra and inter* species competition.

4. Individuals Diverge (mutate/learn), Species Converge (reinforce procreative selection choice/socially engineer) and these reflect that quintessentially dynamic relationship of individual choice versus group selection. Again there is no inherent necessity to kill, or be killed in the logic for all possible genetic programs.

5. Mammals as the dominant phylum of our origin progressed to replace reptiles in great measure because of the short gestational period combined with better protection of offspring as a result of the introduction of social memetics to the speciation event. They also mutated faster because of a general component of that genetic strategy and this allowed speciation to occur faster than the previously stabilized dinosaur populations of reptiles. We inherit this characteristic as the central vector for mammalian divergence as a species.

6. Humans are the vector for the creation of true mammalian dinosaurs, us. In a way if you took the time to read objectively how the fossil record for today would look by the current standard of paleontology science you can understand the image. Regardless of right or wrong in this we Humans have the power as a *species* now to manipulate the balance of all life on Earth. Including but not exclusive to just human populations.

BTW, this didn't just happen but appears to be the consequence of convergence aspects of our species' mutability with respect to our minds, from communications to memetics. The fossil record shows that we have been altering the world for almost fifty thousand years; not long since we were critically closer to extinction twenty thousand years before.

DNA does not require Death to mutate, but Life like Democracy requires *vigilance and sustenance* or it is soon lost. That DNA is a dance with *Death to we part* is not a marriage of the logic of that contest with the necessity of molecular programming for DNA, it is the *Environmental Reality* of the competition for the game that DNA in every living expression confronts. Self aware DNA's best strategy against death is to diversify life into all possible niches for sustenance and defense.

Evolution is the result of DNA seeking an *advantage* for survival from its greatest adversary, Death. Yes when at first you don't succeed try, try again.

[jaydfox]

Evolution is the result of DNA seeking an *advantage* for survival from its greatest adversary, Death.

(my emphasis added)

For all the crap you gave me about anthropomorphizing Evolution, and you say this? )

But seriously, an interesting progression of logic. I will need time to digest.

Jay Fox

[jaydfox]

Your assumption Jay

I don't know whether ASC are more resistant to becoming cancerous than the typical cell. I would assume so,

is a classic example of the reason scientists don't *assume*, they experiment (testing their assumptions ) ).

Given that I am not in a position to conduct such experiments, nor likely to influence those in such a position, I am left with few options. I say I "assume", but perhaps I more accurately conjecture that ASC are more resistant to cancer, and I put forth this conjecture to those who are in a better position to either conduct the experiments, or influence those who can.

At any rate, this quote of yours sums up my feelings nicely:

I am unaware of this being posed as a specific comparative study on the *resilience and resistance* capacity for ESC versus ASC to become malignant tissue. I think the results would be highly informative.

I would add that such comparative a study be done along the line of what Prometheus suggested: ESC vs. ASC vs. non-senescent somatic cells vs. senescent somatic cells.

The object of my question is a little more subtle. Let me rephrase it perhaps: Are the Stem Cells *malignant* or are they becoming the vector of malignancy because the *source of the stem cell production* has been mutated to produce malformed stem cells?

I will admit ignorance in this matter and request clarification. Are the "source of the stem cell production" and the stem cells themselves entirely distinct? I was under the impression that the "source of the stem cell production" was simply a colony (or reservoir, as I've seen it referred to) of stem cells for which mitosis was a never-ending process, and that as stem cells migrate out from this colony (to rejuvinate/repair), they are replaced through mitosis of other stem cells within the colony. Please correct me if I am wrong.

I am however wondering, can and do ASC undergo mitosis after leaving the "colony"/reservoir? If not, then clearly a functional distinction can be drawn between the ASC and the source, even if constitutively they are the same.

BTW, as a note of technical clarification, when I had referred to ASC in my previous post, I was referring to the reservoirs, not the migrating cells.

Outside the reservoir, as far as I am aware, the ASC migrate to where they are needed and then specialize, becoming in effect somatic cells. This time period is short, so outside the reservoir, susceptibility to malignancy is not a big problem. Within the reservoir, where ASC are given both adequate time and repeated mitosis to become cancerous, it is a far greater problem to consider. So it is within the ASC reservoirs that I am interested in seeing the studies performed (though if it weren't too much extra effort/expense, I'd be interested in seeing the results in the migrating ASC as well).

Jay Fox

[Lazarus Long]

QUOTE (Lazarus Long)

Evolution is the result of DNA seeking an *advantage* for survival from its greatest adversary, Death.

*****
Jay Fox comments:

my emphasis added

For all the crap you gave me about anthropomorphizing Evolution, and you say this?

Touché

For lack of a better word let me return to the more orthodox word *selecting,* rather than *seeking* and I grant your point. Selection as *choice* for group and individual behavior is the critical aspect of our differing perspective on Evolution.

Choice involves speculation upon What is the Will?

Here not only Schopenhauer, but Nietzsche belong in the debate for what constitutes *Will* but so do the perspectives of me and the Romantics that see it in terms of The Will to Love as the result of another aspect of will, the procreative instinct.

Schopenhauer reflects the analysis of the strict Individualist Survival Instinct versus the collective Group Selection for Speciation. Nietzsche describes the experience of understanding the relationship of individual to group behavior for the experience of sustained development and acquisition for critical life support matériel, as well as the defensive choices for individual and collective vigilance and expansion.

However I admit readily that there is a vast chasm between such whimsical thoughts and *proof* so I am guilty as charged but offer instead of that word the more orthodox *choice* of idea; selection.

I would also point out we that are seeing the *logic* governing the molecular biology of genetics from different perspectives as well with respect to the relationship of life and death as a result of our interpretation of this distinction for choice.

I have not chastised you so much for *anthropomorphizing* as much as how & why you were doing so logically. After all to be honest how can someone like myself seeking to author a treatise on *Human Selection* be chastising anyone for a position on the simple demerit that it is anthropomorphic. )

[jaydfox]

One way to speed up research in this field is to collect genetic material from distinct parts of the body (bone, Organs etc.) compare and contrast the specialized cells; examining which DNA structures are coated with the protein that makes them dormant. This method will greatly speed up research to map out what genes are responsible for what.



For Skeptics And Interested Individuals.

Various plant life such as trees can live for centuries. Ah, but you may be questioning this; saying along the lines of, that is a plant, humans are animals, we are so different. Wrong! The genetical material is basically the same Adenine ( C5H5N5 ), Thymine ( C5H6N2O2 ), Cytosine ( C4H5N3O ), Guanine ( C5H5ON5 ) are the basis of all living matter. Well, here is another fact, which may be more convincing; Tortoises, which are animals such as us, can also live for centuries. Lobsters can regenerate broken off limbs. Having the benefits, especially form the latter, will give a blind child the ability of sight. A person with missing limbs the ability to be a physically normal human being.

Lazarus, before you merge this topic, I am wondering what will become of the original author's intended questions.

While I am enjoying the debate over what has developed, due to Evolution through genetics/memetics, I am wondering what we should do with the questions of engineering.

For whatever reasons, some of which we've discussed, Evolution did not lead to humans that could regenerate limbs or enjoy negligible senescence, as other species can. A study of the *Evolutionary reasons* why this is so will better help scientists understand the "biological reasons" that it may or may not be a desireable thing to do. Nevertheless, "123456" raised some good questions.

Through genetic engineering, will it be possible to incorporate what we see in the rest of the animal Kingdom? Negligible senescence? Limb/organ regeneration?

If so, in what timeframe could we expect this? Put another way, how much will we have to understand the Evolutionary aspect of these traits before we can safely move forward with the bioengineering of them?

[Lazarus Long]

Jay Fox:

QUOTE (123456)
One way to speed up research in this field is to collect genetic material from distinct parts of the body (bone, Organs etc.) compare and contrast the specialized cells; examining which DNA structures are coated with the protein that makes them dormant. This method will greatly speed up research to map out what genes are responsible for what.


For Skeptics And Interested Individuals.

Various plant life such as trees can live for centuries. Ah, but you may be questioning this; saying along the lines of, that is a plant, humans are animals, we are so different. Wrong! The genetically material is basically the same Adenine ( C5H5N5 ), Thymine ( C5H6N2O2 ), Cytosine ( C4H5N3O ), Guanine ( C5H5ON5 ) are the basis of all living matter. Well, here is another fact, which may be more convincing; Tortoises, which are animals such as us, can also live for centuries. Lobsters can regenerate broken off limbs. Having the benefits, especially form the latter, will give a blind child the ability of sight. A person with missing limbs the ability to be a physically normal human being.

******

Lazarus, before you merge this topic, I am wondering what will become of the original author's intended questions.

I have not heard from 123456 yet but all of what has been written will remain in the thread after I merge and everything from this thread will follow in the same sequence it has now only probably begin after all the other posts appear on the first pages. It is just that the topics and posts there parallel here too closely too ignore. (that is until right after I wrote this [:o]

They overlap but we could start a topic that is focused exclusively on approaches and detailed systemic explanations. Here I am trying to still address the underlying theory but experiments yield possibility of the results being relatively quickly useful.

Jay Fox:
While I am enjoying the debate over what has developed, due to Evolution through genetics/memetics, I am wondering what we should do with the questions of engineering.

Since you ask.

Here is a specific related threads we can use to flesh out the ideas developing in this thread, along with others.

ASK BIOTECH QUESTIONS!

Within a year or two I expect the first positive results of prehuman trials for ex- vitro, and xenogenetically grown skin, teeth, hair, pancreatic tissue, cartilage, bone and perhaps many more specifically targeted organ or vascular tissues I suspect the easy things to grow around a matrix are things like replacement aortas that are DNA matched to the host and can be grown in a reasonable time after diagnosis. Growing the various smaller cardiac arteries too.

I expect methods for repair/replacing more complex parts to come as we learn from the simpler ones how to begin the process and then refine what we learn. After that kidneys, liver, and other parts are not long behind.

I expect many of the first serious human trials to begin to go forward in three to five years from now.

I do not think in all cases we will try and grow the new organ internally and in most cases these will be grown in baths, preparing them for implantation as organized DNA matched parts. I also expect that seeding* will be the case in terms of teeth, hair, and skin because these are items that can heal into place from buds, plugs, and follicles. Why hair you might ask?

Because it pays for the work and teeth because it is obvious and comparatively easy. Skin is also a great way to build a methodology for large scale tissue growth with minimum complexity and take advantage of the fast growing ability for stem cells to be cultured and develop the methods of stimulating various growth models.

I think the possibility of building neural tissue implants and complex structures like spinal columns are still a ways off but not out of the realm of possibility.

Bio-Engineering negligible senescence is not as easy as cosmetic surgery but the demands of that medical sector will merge as the control of over tissue growth is paramount to the possibility of replacing scarred tissues with new ones that are actually transformed into younger tissues and I wonder as I have also suggested if the medical fields of oncology, virology, and autoimmune/genetic disease are all going to merge under a growing unified genetic based doctrine that will even merge old time germs theory through how protein interaction happens at the molecular level.

The isomeric character of antigens is already a known fact and now we also know why specific sequences of genome are vulnerable to the keyed shape but a whole new way of integrating and looking at disease is developing and that includes acknowledging that again is just another disease to fight.

As for Xenotransplantation of specific sequenced characteristics I expect that with one to two generations. This approach will require far more safety measures up front and a lot more subtle control of the product but one method I already suggested is to use the fight against some forms of cancer by altering the hosts genome a little and the tissue of an effected organ a lot.

The Prostate and Skin might be organs that merit testing in the capacity I suggest earlier. I wonder if the biopsied malignancy can have the hosts DNA sequenced with aspects of the cancer and the xenologically defined sequences for that organ tissue replacement (prostate in this case). Son through proteomics will be able to artificially construct the target sequences if we have a blueprint to follow. This should help prevent the piggybacking of cross species retro viral infection.

If the cancer tissue could through a stabilizing characteristic from another species begin a regulated growth and act *like* a stem cell replacing original cell apoptosis with the up regulated cells. If the malignancy retains sufficient DNA of the host then a body match might not trigger a rejection problem and the immortalized tissue might even in the case of the Prostate for example, naturally shrink for a number of years.

The common *natural* forms of cancer that effect the prostate and skin are often age related and are isolated slow growing enough that optional methods can be attempted without the procedure being instantly life threatening.

BTW another tissue I expect can be grown externally and then implanted is intestinal tissue and a lot might be grow to replace a radical resection of the bowel or other sections, this might also work for bladders. Are the trends I am implying too impossible to imagine?

I actually think many of them are quite logical once you think about it.

Edited by Lazarus Long, 25 August 2004 - 03:56 AM.

[jaydfox]

Whilst we are (were) on the topic of anthropomorphizing, may I suggest my controversial 2 cents worth: Death is but a servant of the real enemy - Evolution. You can plainly see that it is evolution that requires that we become senescent and die. It is evolution that requires that we be subject to mutation, disease, cancer, and death. Once, of course evolution was our greatest ally and shaper of our destiny. Alas, we have outgrown her ministrations.

You know, I've been wondering something about death's role in Evolution. While not a biologist, I can see several *benefits* of death, or of processes like mutation/disease which lead to death. I'm not saying that these are the benefits for which Evolution "justified" "allowing"/selecting for death to be programmed into us (though I believe this to be the case). (BTW, I love being able to anthropomorphize an intent to intend: Self-aware Evolution! [tung])

One such benefit is that mutation allows evolvability, a highly desireable fitness trait. While mutation in practice leads to cancer and death, I am wondering if it must be so. We already know that gene expression profiles vary from organ to organ, and indeed from tissue to tissue.

Why not arrest the process of mutation throughout the body to the best of the DNA's theoretical ability, but allow mutation in the sex organs. And not in the entire sex organs, as that would eventually lead to malfunctioning sex organs. Why not keep even the stem cell reservoirs defended as well as possible against mutation, but allow the next step towards meiotic cells to allow mutation (the "good" forms of mutation preferably), with a sufficient time lapse before actual post-meiotic cells are produced to allow mutations to occur?

Perhaps I'm not suggesting this so much for Evolution, since it's a bit late now, as much as for our future self-directed evolution (little "e").

However, given Evolution's ability to specialize on a tissue by tissue basis, combined with my belief that mutation is suffered to happen in order to promote evolvability, leads me to believe that mutation/cancer/death have a purpose beyond mere genetic variability: death itself is a key element of evolvability. It is not just the mutations, but the death, that are required for evolvability.

Just my two cents. )

Jay Fox

Edited by jaydfox, 27 August 2004 - 05:38 AM.

[Omnido]

1. Are you talking about changes to sequence, methylation or histone patterns? The cell is not as tolerant to DNA sequence change as you suggest. The usual outcome of such changes tends to be apoptosis or cancer. You may want to clarify that statement for your audience.

There are many alternate proposals which have been theorized for quite some time. One of the most common utilizes the current methodolgy of Gene therapy, in which the patients own DNA is reconstructed into a type of Retro-Virus that is used to safely "Infect" the patient, and replace the existing DNA with the re-sequenced DNA. This method inandofitself, combined with a few other simple treatments, i.e Telomere regeneration, would more than suffice to prevent DNA degeneration and mutation.

Digitizing the Human DNA code is simple. We've already accomplished that.
Synthesizing it is a tad more difficult, but technologies are developing that will allow this to become quite easier as the years progress. The concept that each and every individuals DNA can be digitally stored and then recreated at will by technological means, is more than sufficient evidence to warrant what I like to refer to as: DNA Retroviral-Reinfusion.
And thats only the beginning...
Something as inherently simple as Gene-therapy and Telomerase treatment could inandofitself solve a multitute of cellular aging problems.

2. You make it sound like it is merely social issues that are occluding scientific progress. Our "vast technological abilities" remain speculative until proven otherwise. We have yet to demonstrate even the most rudimentary effects of lifespan extension other than the ineffectual manipulation of CR type mechanisms. You must be aware of alternative methodologies. Let's hear them.

See above.

Im not suggessting that this is a bag-in-the-hat procedure or process. However, DNA is merely chemical information. It can be treated with the same degree of finite precision as digital data, with a methodolgy that resembles "Digital Sampling" at various tolerable "Bit-rates". When we have the precision to work with chemistries capable of viral engineering and Gene-Therapy, the prospect of total Genetic digitalization does in fact become, a bag-in-the-hat, given just a small amount of collective effort and a unification of the various disciplines needed to accomplish it.
Such efforts are being put to use by the Computer Engineering industies of IBM and other corperate giants, and the advanced precision micro-technological engineering sciences that are already being put to work at Lawrence Livermore National Labs, to name just a few.

The real problems arise when social, political, and capital powers are the ones responsible for the unification, or lack thereof of the aforementioned disciplines. Unification within the scientific community has been scarce at best, unless there is a global threat that would require the immediate collaboration of the brightest inventive minds on the planet.
This was done before Hiroshima, and that was the last time a group of such said minds congregated with urgency to solve an otherwise impending serious global threat.

One of the problems of society however is, necessity is the mother of invention. You never really look for something, until you need it.
This trend has continued, and will no doubt continue until a social revolution takes place that will warrant the need for said unification.
History has demonstrated this repeatedly, and will no doubt continue to do so.

[DJS]

However, given Evolution's ability to specialize on a tissue by tissue basis, combined with my belief that mutation is suffered to happen in order to promote evolvability, leads me to believe that mutation/cancer/death have a purpose beyond mere genetic variability: death itself is a key element of evolvability.  It is not just the mutations, but the death, that are required for evolvability.

What has caused you to arrive at this "belief"? My perspective seems to be the opposite of yours on this matter.

I have yet to see any evidence of a "life force" which decided that mutation was a good thing. The reason that life can evolve is because mutation is a naturally occuring phenomenon and indicative of the imperfect nature of replication. Mutation doesn't happen because of evolution. Evolution happens because of mutation! The most that evolution can hope for is to influence the rate of mutation to suit it own ends (ie; slow it down or speed it up).

Likewise, senescence doesn't happen because of evolution. Evolution happens because of senescence. In this case, the most that evolution can hope for is to influence/regulate the rate of senescence via protective mechanisms.

It should be obvious by now that this can really be argued either way and as has been suggested, we find ourselves in a chicken/egg delimma. This is why we need to analyze our underlying assumptions and better utilize evolutionary biology.

DonS

[Lazarus Long]

It is not that a "life force" decided that mutation was a good thing - it was selection. Organisms that were able to change their DNA (mutate) were selected for survival over organisms that could not mutate. Also particular rates of mutation were favored over others in the context of how quickly an organism needed to adapt to changing environmental circumstances.

Senescence is a result of mutation. Note that the rate of mutation is proportional to the rate of evolvability. Senescence is a result of evolution. Cells become senescent in order that they do not become carcinogenic. The senescence pathway is activated once a certain amount of DNA damage occurs. It is a fail-safe strategy designed to protect the survival of the organism from being overwhelmed by tumors. Of course, the result of senescence is also eventual death.

More importantly, this is not a matter of the 'chicken or the egg' because we know single celled organisms such as bacteria are potentially immortal - in fact one could say that all simple life was originally immortal. But the genome had to become destabilizable in order to be able to be mutated. The very genomic plasticity that enables evolvability creates the vulnerability to senescence and death.

Finally yes this is the crux of the matter IMO too Prometheus because it shifts the debate to one over *complexity* rather than just mortality per se in terms of DNA encryption and interactive behaviors (a long versus short term result). You see it does suggest selectivity for complexity but it is still arguably because even that nearly *immortal* DNA, as it colonized the entire biome, was both simultaneously mutating and experiencing mortality in the struggle to survive and the result is the development of counter strategies that co-opted senescence for strategic advantage.

Now I admit up front I prefer better language than *strategic* but it is almost impossible in human language to discuss the gaming aspects of evolutionary theory without its inclusion. Where there are strategies that seek goals; how can we define goals without discussing *imperatives* (be they logically requisite, inherent, or consequential) ?

So is there an imperative for complexity derived of the intrinsic characteristics of competition for survival combined with procreative competition that reflects the divergent aspects of individual DNA mutability?

Again this returns to the axiomatic relationship of what I assert are the dual competitive evolutionary aspects described in DNA's apparent group and individual character: Individuals Diverge and Species Converge.

I intentionally imply that *Species Converge* rather than being just the *result of convergence* because I am suggesting a more dynamic and complex strategic advantage of *numbers*, which over *time* for various types of generalized *collective selection* may be at work. A process that we see for all living behavior down to the expression of the most primitive bacterial *colonizing* behavior.

These dual aspects of Evolution may reflect a dual core set of logically dependent behavioral subroutines for the relativism of group and individual combined gaming and this characteristic may be derivative of the dual aspects for survival of the fittest strategy combined with procreative selection strategy as a primary encrypted logic for all *self organizing* (perhaps a better way of saying self aware) DNA. All DNA that is *self organizing* can develop into a being of some sort and those that are *viable* are also capable of procreation and these individuals might be better understood as archetypes.

The dual strategy of DNA is more than a safeguard (fall back) and this may be the core competition, which both aspects are focused on by overcoming death together by a combination of individual (short term potentially disposable mutability) and collective (long term reinforced speciation) because almost immortal is still mortal.

I will add that individual cellular *specialization* parallels in both evolutionary competitiveness and complexity the *spoliation* of individually defined DNA phyla. This was *why* people thought for years that Ontogeny recapitulates Phylogeny and in a way there is still some truth to the idea when examining the combination of fetal development, tissue differentiation, procreative strategy, and social behavioral capability.

I happen to also think that there is a strong argument for strategic senescence at the cellular level, apostasies being an obvious example, but still due to the complex length of the evolutionary record see this as a response to mortality rather than making mortality the objective per se for any given level of complexity.

Also at the sublime level of DNA *self correction* it is representative of the group demand for genetic conformity over the individual mutability. However as the vast majority of mutations are negative this weights as a prejudice against individual mutation in the risk/rewards relationship, so collective DNA speciation selects against the expression of all mutation and only the most potent forms express and these in turn are then winnowed in or out of the DNA paradigm that defines the self corrective species model through *long term* group selection over time, which is in turn the result of reinforced group selection models creating Convergent Speciation for any given *environmental* specialization advantage. The individual *archetype* of any species paradigm is not just a viable individual DNA but a result of group pressure that drive the creation *species*, as a result of the generational pressure to efficiently converge on any specifically selected environmental niche.

The reason I and perhaps many others, see this still as a form of making a devil's bargain is that it doesn't make death an objective, or even necessary, but it is being implied by some to be a *necessary opposite* and used to *justify* the competition as necessary to evolution almost as an *end* in itself. I am suggesting that destroying a cell in the manner of apoptosis to save the larger more complex organization should not be presumed as making death necessary for evolution but evolution's answer to Spock's challenge of "the needs of the many outweighing the needs of the few."

We must also IMO begin to see the complex relationship of cell differentiation that genetically defines a *total being* (archetype) as not only creating a competition between the needs of an individual cell (soma) versus the total *archetypal* being but also as a the result of a type of *internalized* evolutionary process that parallels (not mirrors) the externalized one. And *species* should in my opinion be better defined in terms of genetic *paradigms* that result from the biophysical relationship of the *archetype* to the environment. Individuals can then be treated as archetypes and species as paradigms for the algorithmic logic of DNA, and combined with *mutability* creates a fluid adaptive relationship resulting in the evolution that we see but now might also begin to define.

Being faster at mutation allowed for the faster recovery from catastrophic environmental shift and as we can also see from the fossil record this dynamic for natural selection is at work too. It contributed to rise of mammals, and in turn ourselves. The downside of possessing a more stabilized mutation process was also the earlier senescence of the paradigms' archetype: BUT NOT AS A CONSEQUENCE OF FAVORING THE PARADIGM AS SOME ARE IMPLYING.

Cell apoptosis is possible to *preserve* the archetypal individual DNA (along paradigmatic species definition) as long as feasible by sacrificing parts to preserve the whole, which in turn results in death by attrition. Cancer on the other hand may then be seen as a runaway *adaptive* mutation process that was our mammalian advantage as a phylum being pushed to its paradigmatic limit in our species because of our combined success as archetypes in the competition under Natural Selection. One aspect of that success is the intelligent recognition that we are shifting the rules for defining selection from Natural Selection to Human Selection commensurate with the shift from genetic to memetic paradigms for defining archetypal expression; hence *Transhumanism*.

We simply were too short lived as a general rule to generally encounter the limits of our paradigm until our species was successful long enough and had developed sufficient advantages that then exposed them. Until very recently most humans never lived long enough to really worry about senescence from cancer, cumulative cell damage produced its result at an earlier age due to the significantly higher levels of environmental stress.

I would argue that evolution may be better understood as the result of both the imperative to survive for all *self recognizing* DNA archetypes combined with the long term group selection mechanism that is selecting for *complexity* by virtue of the relationship of complexity to intelligence. Intelligence combines advantages for both survival and procreative strategic ability. Thus it is by a somewhat different path that I am coming to a similar conclusion as John Smart for example but it will be a unified mathematical model for Evolution combined with Genetics that ultimately will provide a conclusive answer I think.

Edited by Lazarus Long, 31 August 2004 - 12:29 AM.

[Lazarus Long]

This prompts the question: what would the effect of an enhanced level of DNA repair be and why is that cells have not evolved better strategies of genome maintenance? As supported by experimental evidence, it seems that with enhanced genomic maintenance the incidence of disease would decrease, the onset of senescence would be delayed and the organism lifespan would be increased.

Actually we see this in other species like some reptiles, arthropods, and plants. They stabilize their genetic paradigms to a given particular environment. These living dinosaurs don't mean that evolution is dead ended for them only that like sharks, they are the pinnacle of environmental specialization and other species will converge on this paradigm only through an advantage derived from the complexity of intelligence and social advantage.

The mechanism that directly links the rate of mutation or evolvability to aging is the rate of DNA repair versus DNA damage.

Numerous studies now support the view that DNA damage is the cause of cell senescence, disease and aging. The rate of mutation is inversely proportional to the cells ability to repair alteration to its genome. When DNA repair mechanisms are upregulated the rate of mutation decreases and the onset of senescence is delayed. Conversely, when DNA repair genes are knocked out the rate of mutation increases and premature aging ensues.

In order for a rate of evolution to be maintained at a rate suitable for survival a cell must balance its genome repair and maintenance processes against mutagenic forces including those that result from metabolic by-products and those that are caused from the environment such as UV radiation. What we see in the cell is that when DNA damage is accelerated by mutagens we get increased expression of DNA repair factors. This suggests the DNA damage/repair rate is homeostaticaly regulated like so many other processes.

I completely agree. The point I am making is to question whether you and others are reading in consequence to what may be considered a coincidence.

The answer is that it would slow down the rate of evolution and evidently the price of extended lifespan and robustness in later years is too high to pay if it comes at such a cost.

A faster rate of mutation should not be confused with evolution per se, it is only an advantage when put in a human perspective for time and any given paradigm is challenged by catastrophic force. Mutability provides a better chance for recovery but the vast majority of divergent evolution is simply the replacing of former species' paradigms that filled the same environmental niches. Complexity is the additional quandary because when we introduce *Selection for Complexity* we are altering the basic paradigm of evolution away from strict Darwinian parameters.

Evolution is not inherently a progressive process, it is a *stabilizing one* that is altered by catastrophic intervention when the entire fossil record is examined. Once the most successful paradigms result in environmental dominance for resources these paradigms remain extant until supplanted by another that separately evolves to competitive advantage on separate continents that through tectonics are merged and then overtakes it, or when all the dominant groups are destroyed when the ecological deck is shuffled by catastrophic environmental shifts caused by climate, volcanism, cosmic event, or perhaps pandemic and this results in a sort of evolutionary reboot with new players and strategies coming to the fore.

It is this last aspect of competition for available resources that always brings me back to using economic models for better understanding the rules of the competition for Natural Selection and why I try to talk in terms of Environmental or Evolutionary Economics. For example, to throw fuel to the fire the competition between capitalist and social economic modeling reflects a very similar kind of resource competition between individual and group selection methodologies both for *intra and inter* species competitiveness.

[DJS]

It is not that a "life force" decided that mutation was a good thing - it was selection. Organisms that were able to change their DNA (mutate) were selected for survival over organisms that could not mutate. Also particular rates of mutation were favored over others in the context of how quickly an organism needed to adapt to changing environmental circumstances.

This is a excellent point and has improved my understanding of the issue. What I was objecting to in my initial post was ambigious wording that led me to believe JDF was proposing that mutation was "created" by selection. This is patently false and you have subsequently clarified that which I was misinterpreting:

The mechanism of mutation is what enables evolution to take place. This is axiomatic.

[jaydfox]

This is a excellent point and has improved my understanding of the issue. What I was objecting to in my initial post was ambigious wording that led me to believe JDF was proposing that mutation was "created" by selection. This is patently false and you have subsequently clarified that which I was misinterpreting

Sorry if I wasn't clear about that. Allow me to try to go back and clarify.

However, given Evolution's ability to specialize on a tissue by tissue basis, combined with my belief that mutation is suffered to happen in order to promote evolvability, leads me to believe that mutation/cancer/death have a purpose beyond mere genetic variability: death itself is a key element of evolvability.  It is not just the mutations, but the death, that are required for evolvability.

I will try to reclarify. Mutation obviously is allowed to happen at a greater rate than required; the fact that DNA repair can be more efficient during stresses such as CR demonstrates this. So, there is very little room to argue that better DNA repair is not possible. However, it was selected against, and this too is obvious. However, the question is, why?

Prometheus and others have argued that mutations are allowed in order to promote evolvability. I don't disagree with this point. If, by the way, you accept this point of view, then clearly evolution has selected for aging phenotypes, even if aging was a coincidence of this selection, as opposed to being the justification for this selection. This goes back to the debate that Lazarus Long and I have been having. Clearly, a higher than necessary rate of mutation was selected for, but was aging selected for, as I believe, or was aging merely a coincidental side effect of selecting for mutation?

Which brings me to the point of the sentence you quoted: gene expression varies from tissue to tissue, organ to organ, throughout the body. Evolution has been very good at selecting for processes that allow multiple gene expression profiles. Which makes me wonder: if mutation was selected for, presumably because of its benefits for evolvability, then why wasn't it selected for to only be expressed in the sex organs? Why can't the rest of the body be better protected against mutation than the sex organs?

Evolution, as far as I'm aware, clearly could have selected for this, but didn't. Which leads me to believe that mutation was selected for, not merely for increased gene variability within offspring, but also because the process of senescence, and by extension, death, was beneficial.

Jay Fox

[Lazarus Long]

Ask and ye shall receive Prometheus )

Here is an interesting finding that goes directly to the issue you raise.

http://story.news.ya..._cancer_gene_dc

BTW, I have written some extensive replies to your last posts that I will edit and pare down before posting. But this conversation is definitely building to the correct focal point in my opinion as the question are not only on target but they are generating answers that are increasing the precision of understanding this complicated matter for us all.

Scientists Identify 'Jekyll and Hyde' Cancer Gene
Wed Sep 1, 2:11 PM ET

LONDON (Reuters) - French and American scientists said Wednesday they have identified a "Jekyll and Hyde" type of cancer gene that could lead to better ways to diagnose and treat the disease.

Unlike other cancer genes that either promote cancerous tumors or block their growth, researchers at the University of Lyon in France and the Buck Institute in Novato, California have found a gene that does both.

The gene called DCC is a receptor on the surface of cells. It was thought to be a suppressor gene that stops cancerous growth but the researchers discovered that it could be switched to promote cancer by a protein.

"This new line of research holds promise for potential therapies or predictive tests for cancer," said Dale Bredesen, president of the Buck Institute and a co-author of the research published in the science journal Nature.

DCC usually acts as a brake and stops cancerous cells from proliferating and causes them to commit suicide. But when the growth factor protein called netrin-1 is abundant the brake is removed.

In a study of mice genetically engineered to produce high amount of netrin-1, the scientists found the animals had a high rate of precancerous growths. But when they combined it with a genetic mutation that causes benign tumors, the mice developed colorectal cancer.

"Detecting abnormalities in levels of netrin-1, or other similar molecules, might help us identify those patients at risk of developing malignancies; furthermore, by manipulating the abundance of netrin-1, we might be able to stop the cancer in its tracks," said Bredesen.

Although the mouse study involved colorectal cancer, Bredesen and his French colleagues said the finding could be applicable to other types of cancer.

"This interaction described between a particular receptor and growth factor in digestive tumors is probably true for other pairs of receptors and growth factors and for other types of tumors," Patrick Mehlen, of the University Claude Bernard Lyon 1 in France, said in a statement.

"This observation should lead researchers to look at cancer development from a completely different angle," he added.

The scientists believe DCC could be the first of a number of conditional tumor suppressors. 

Let's try and get some links to more in depth material on this regulator gene that influences cancer growth activation. Those of you with access to actual texts please share the wealth.

[Lazarus Long]

Even though you edited out this comment Prometheus I am going to answer it by way of tagging this issue even further for as you say it is getting nailed down.

For clarification, LL, can you state which two specific events you see as coincidental (and I et al see as related)?

I am referring to the relationship of cell mortality or senescence more specifically, and generally even our mutability to *evolution.*

I am arguing that the nature of the causality does not make our *evolution* consequential of cellular senescence but coincident to the good fortune of being mammalian in the aftermath of the KT event, because the mammalian advantages of *mutability* (that are as you described) provided an initial competitive edge in the divergent period that ensued.

I am also suggesting that cell senescence is the result of DNA trying to sustain the specific individual expression as long as possible but not that it requires apoptosis for more than elimination of damaged or mutated cells and that actually apoptosis is a natural balance against mutability and mutability is mixed factor that is only a positive factor in evolution by default and as balanced against the generally dominant effects of apoptosis.

In other words to introduce a variable that is ignored by the more *orthodox* Darwinists, I suspect an adaptation to *catastrophism* is at work that has been influencing the *rate* (and as a result the rate of mutability) of evolution through the group selection pressure to converge on potential new environmental niches.

The reason I suspect this is important is that it should describe a result very similar to what a fossil record shows as I am saying that Divergent individual mutability is opportunistic but Convergent speciation is a stabilizing force and at any given point for any individual set of genes in a larger genome these two dynamic forces are in a tug of war creating a potentially divergent, or convergent weighting of the species' specific genome character based on environmental conditions and specific *opportunity*.

[Lazarus Long]

Prometheus said:

The answer is that it would slow down the rate of evolution and evidently the price of extended lifespan and robustness in later years is too high to pay if it comes at such a cost.

*Evolution* neither progresses at a constant rate when seen over the long run (as you later noted as well) nor does it require the most successful species in one environment or period to be the prime vector for the evolution of all life, or even its own phylum.

I suggest alternatively that evolution is always rapid (accelerating) during the initial period of divergence *necessary* (reflecting a higher degree of mutability) to fill environmental opportunity (niches) and then always slows down after the maximization of optimal paradigms for species expression of successful convergent physiology. Afterward *Evolution* has routinely naturally slowed into a relatively steady, almost homeostatic state once species become optimized. It is then that individual longevity can and often does result.

In other words evolution does not depend *specifically* and consequentially on the mutation rate but is coincident with environmental opportunity available for the application of the mutation. The level and character of the competition to survive is incorporated into the convergent drive of speciation as well based on supply and demand for environment.

It is a very human characteristic to combine the ideas of learning and change with evolution as if it too were *progressive;* it is not synonymous. *Progressive Complexity* may be a *consequence* of evolution but evolution is not singularly a consequence of the tactic of senescence. In other words while progress at times may be seen as a consequence of Evolution, evolution is a coincidence of factors that include physiological *progress* (including intelligence) AND environment appropriateness.

I am saying that cell apoptosis does not mean cells could not also evolve to replace themselves ad infinitum. The real issue is *mutability* as you suggest and this is *coincident* of us being mammalian that was a coincidence of being more adapted to a post cataclysmic environment that under no system of Natural Selection could have been anticipated or selected for evolutionarily.

I am suggesting that when we really look at the great epochs of evolution they all demonstrate a similar pattern of initial divergence, which results in optimization for speciation that stabilize into long periods of lessened change that are ended catastrophically. The catastrophes initiate (cause) the reorganization of the entire biological competition (global ecology) and are not something that DNA is *programmed* specifically to select for because it isn't an environmental constant, nor an obvious environmental condition.

Strict genetic modeling can be understood to treat catastrophe as an opportunity to restructure the survivors into a new more complex competition for remaining resources and this implies a type of long term selection for complexity as a result.

I am also suggesting that slowing down mutability is something we also see in *evolution* once a paradigm settles into an optimized role for the selected environment and while mammals generally are no different, humans are. Basically to return to the initial inquiry, the Eukaryotic ability to defend the total being against unregulated and destructive mutation resulted in the evolution of cellular senescence (apoptosis) not that cell apoptosis resulted in evolution, And secondarily that sexual reproduction down to the level of plasmids are the prime method of regulating mutation and incorporating the potential advantages into the germ line of any given species

We have shifted the rules by altering environment instead of just adapting to it. We have also begun a more important paradigmatic shift to a (human) memetic based imperative for evolution so long as our species continues to exist and dominant the global ecology. Now add to this the ability to reorganize and self define our own archetypal expressions of the human paradigm.

(BTW I am not suggesting we humans abdicate our dominant position either but rather that we understand and acknowledge our responsibility by adapting to and adoption of the meme of noblesse oblige).

Additionally there is a significant period of time between the initial Precambrian mutation into Eukaryotes and the Cambrian Divergence and I am suggesting this is explained by the Environmental Economics of available resources. A relativistic competition that suppressed divergence in favor of homeostasis until an external catastrophic factor altered the rules of the game. There is now growing evidential support for such a cataclysmic event as well.

After the event Eukaryotes with higher order complexity and mutability could diverge rapidly replacing the dominant protozoan life forms and even feeding off them in the process. Multicellular life then goes forward with a number of periods of rise and fall for various dominant forms that all now appear to be punctuated by latent forms of one period becoming dominant in the aftermath of some form of climactic paradigm shift that alters the basis of competition.

Cell apoptosis reinforces the status quo of the species' DNA paradigm and suppresses the expression of individual mutational archetypes. Hence I see a balancing act at work that results in the evolution toward a stable form that is environmentally *optimized*. So if my assertion that Individuals diverge and Species converge then the way this occurs naturally will be by weighting the ability of mutation to express and yes the result of optimized speciation will also be the concurrent increase in the evolution toward individuals of longer life span but less mutation, conversely as environment offers divergent opportunity mutation rates increase and longevity is reduced, but survivability ins a severely altered environment is also likely to result in a higher mortality for any species optimized to a significantly different prior environment. Hence this balancing between increasing/decreasing rates of mutation are consequential of the environmental pressure (increasing/decreasing opportunity) to either diverge or converge and this weighs coincidentally on the *rate* of evolution.

We have basically outlived our heritage but we are not the first species to do so I suspect. We are living long enough to push our genetic envelop and this crates the pressure to shift the model from the mutational divergent one to the species stabilized (or optimized) long lived one.

Earth’s next major phase of both divergent and convergent real evolution will likely be through our (human) intentional memetic driven optimization of our own genetics, not based on the *coincidence* of environment and mutation. This reflects both intentional convergence on a maximized or optimized *human paradigm* and the divergent ability to modify our, and any other species, so as to insinuate itself into alternative environments from marine habitat to other worlds; however this is no longer the *non rational* result of the aforementioned Darwinian coincidence of selective factors but a highly rationalized and human defined one.

The upcoming period of biological reorganization for our species in its turn will likely be followed by a cyber-synthetic one, still driven by memetics and derived of our ability to apply our technological advantage and environmental controls. We are the vector species of the paradigm shift for evolution from genetics based evolution to memetic based evolution that creates a rational imperative for it and sets its own rules with respect to viability and requisite mortality. As this occurs it basically makes moot the distinction I am making about *coincidence and consequence.*

[jaydfox]

The catastrophes initiate (cause) the reorganization of the entire biological competition (global ecology) and are not something that DNA is *programmed* specifically to select for because it isn't an environmental constant, nor an obvious environmental condition.

Admittedly, the first couple catastrophes might not have been an "obvious environmental condition". But over the eons, the catastrophes continued to happen. Some were global in scope and lasted centuries or millenia. Some were continental/regional, and lasted decades, and some lasted only years. The ones that lasted only years or decades happened quite frequently on a geological time scale, and these did *become* obvious environmental conditions.

Mini ice ages, centuries-long environmental conversion from rain forest to desert, grasslands to tundra, etc., and back again... These things kept the DNA on its toes, so to speak, forcing most species to maintain some level of mutability. Those species which adjusted too much to the current status quo, and sacrificed mutability for longevity, did not survive in the long term, so that *multiple redundant* mechanisms of enforcing mutability, and by extension, senescence and death, we selected for.

A sufficiently long period of calm can slowly undo these multiple redundant systems, but that they are so well conserved across species today implies that, coincidentally, such a period has not existed that often. Surely, statistically speaking, such periods have existed, and we could hypothesize that lifespans became greatly extended. However, even as lifespans lengthen in the absence of environmental catastrophes, we should in no way assume that a form of static equlibrium would result. At best, we can expect a dynamic equlibrium, where species continue to evolve in the absense of environmental pressures.

From the point of view of a supposedly well-adapted (static) species A, the competing species B and C may evolve advantages that change their role in affecting the well-adapted traits of species A. No species lays claim to the phrase "optimally adapted" without in some way being dependent on the characteristics, good and bad, of competing and symbiotic species. Should changes occur in one species, changes may be required in several others. With so many species across several phyla competing and cooperating, it is doubtful that a truly static equilibrium will ever be achieved. And then throw in environmental disasters of varying degrees and lengths, and mutability (and by extension, death) will never truly be selected against for the vast majority of species.

Obviously, there will be the very few species, and even orders or classes, which evolve significantly lower levels of senescence. But for the broad range of species, we would *expect* what we observe today: mutation, senescence, *programmed* death.

However, as Prometheus pointed out, as far as we're concerned, the important issue isn't necessarily why. It's simply how. How does aging work from a "programmed" perspective, and what can we do to undo this programming?

Of enormous importance, though, are not the evolutionary implications which are interesting to contemplate, but the promise of anti-senescence interventions that can be developed based on this knowledge.

Jay Fox