• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
- - - - -

Improving SENS? Breaking it down...


  • Please log in to reply
20 replies to this topic

#1 jaydfox

  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 February 2005 - 09:35 PM


SENS. This is the first of what will hopefully be many attempts to break down the aspects of SENS, scrutinize and describe them in terms suitable for well-educated layman, and then judge the currently suggested solutions. If the current solutions are optimal, then we've bolstered an important program. If they are inadequate or have competing solutions that can be presented, then we have the basis for ensuring that, should de Grey's program move forward, we have ideas on the back burner. Who knows, we might even come up with something more suitable to the problems at hand.

Dr. Aubrey de Grey has laid out seven causes of aging, and one or more solutions to each problem. Well, with debates happening recently, there have been some asking for details on how to fix SENS, if we perceive problems. In other words, don't just criticize, but offer a solution.

Well, I'll start with one of my own, based on reviewing the debates of the last week and of the last year.

7 points. Okay, basically the same. We outline the same seven causes. This is an important base, because if no one disputes it, then we have outlined the basis for competing SENS theories, and we can let the scientific marketplace battle it out and take the best one to three winners when the dust settles. Then we're not dependent on the scientific judgment of a single man, regardless of how brilliant he is. Putting all our eggs in one basket is a bad idea when 100,000 lives a day are at stake. If it's all we've got, and if unity of message brings us funding and public acceptance faster, that may alter the equation. But from a purely scientific perspective, we need to foster competing strategies if they can be as rigorously defended.

Okay, with the seven causes in place, we need to go a little bit deeper. I will use only chromosomal DNA as an example, because it's the one that I have the best understanding of, and there are already competing ideas on the table for how to fix it.

#2 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 February 2005 - 09:35 PM

Chromosomal mutations.

DNA mutations in all cells build with time, at least linearly (assuming a static rate of net damage) and at worst exponentially, assuming a feedback of existing damage that allows and/or causes further damage. (actually, the worst case scenario is doubly exponential rate of damage, which assumes a non-linear, possibly exponential rate of damage based on the amount of existing damage. I doubt this. I would accept at worst something roughly related to the gamma function, more than merely exponential, but not doubly exponential. But I digress...). The actual rates will vary from tissue to tissue, but within each tissue, we'll have at least a linear buildup of DNA damage with age.

Assuming even linear damage, we can see that, with time, DNA damage will eventually render all cells inoperable: some organs before others, but eventually all of them. This is not even including the problem of cancer.

So, we have to replace the DNA. That much we know. Now, what are our options?

0) Prevent the DNA damage in the first place.
1) Replace the DNA of every cell in the body.
2) Selectively kill (ablate) cells with the worst DNA integrity (i.e. most likely to be cancerous, precancerous, senescent, dysfunctional, etc.), replacing them with cells with better DNA integrity. The body already does this on a limited basis through apoptosis and replacement by stem cells.

Okay, option 0 is a red herring: it is not a long-term solution. We'll assume for the moment that achieving zero net DNA damage in each and every one of the hundreds of trillions of cells in the body is virtually (but not absolutely) impossible, and practically impossible given the technology of the next 50—if not 100—years.

Okay, what about option 1? This one's tricky, as it also happens to be a proposed delivery method for genetic alterations, not just genetic repairs. At any rate, this would need to be periodic, since we've already accepted that option 0 is not a long-term solution. However, as a note of interest, item 0 can decrease the frequency of performing option 1 (and option 2).

Now under 2, we have ablation, and we have cell replacement. At this point, it should be obvious that these two can be separated.

Ablation: 2.1
Replacement: 2.2

Okay, now, how can we ablate cells:
2.1a) eliminate telomerase. All cells exceeding 50 (or another arbitrary number) of divisions will ablate through existing processes for dealing with loss of telomeres (apoptosis), or through sheer catastrophic dysfunction.
2.1b) Increased expression of genes that regulate cells that have problems such as loss of DNA integrity: tumor suppressors would be one example category.
2.1c) Surgery. Useful for limited categories of cells, and covered under a separate item of de Grey's seven points (the "too many cells" category). At any rate, surgery would be too broad in its targeting, as senescent and dysfunctional cells can be interspersed with otherwise normal cells.

Now, how can we replace cells:
2.2a) replacement with existing cells that have better integrity (e.g. stem cells). As a long term strategy, this would necessarily be incompatible with 2.1a (as ALL cells, not just those with poor integrity, will eventually undergo apoptosis), and complementary with 2.2b.
2.2b) replacement by an external source (e.g. reseeding stem cell lines). This would work with either ablation strategy, though it is necessary for 2.1a.

#3 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 February 2005 - 09:36 PM

Okay, now, once we have competing ablation and replacement models in place, we can advocate one. It is at this point that de Grey is free to argue for 2.1a and 2.2b. However, by not even properly outlining it in this fashion, he is doing the scientific community a disservice. Once we agree that other serious options are on the table, only then do we argue for one or another. Not properly laying out our options seems a little shortsighted. This may be one reason why the word "myopic" has been tossed around by others.

Now, I am all for WILT if, and only if, it can be reasonably demonstrated that 2.1b, 2.2a, and 2.2b/1 is intrinsically far inferior to 2.1a and 2.2b.

Here's how I see it. de Grey favors 2.1a because, in addition to addressing the problem of chromosomal DNA integrity in general, it also solves the cancer problem, in his own scientific judgment, orders of magnitude more efficiently than existing cancer therapies. The degree of effectiveness depends largely on the length of telomeres and consequent frequency of 2.2b, so an arbitrary degree of superiority over present cancer therapies can be achieved (though the issue of medical malpractice raises a practical concern, as does cost, which implies a point of diminishing returns on trying to avoid cancer).

And, most inconveniently, 2.1a sets up a situation where people will die without regular 2.2b treatments. And I don't mean they'll die because the effectiveness wore off. I mean a person with 40 years of remaining life expectancy can have that reduced to 15. A huge philosophical problem, in my opinion, open to all sorts of bad problems. Just to name one: suppose a short period of world economic depression interrupts the ability to administer WILT reseedings for a period of 20 years? The rich might be okay, but the majority of people who had received the treatment would be screwed.

#4 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 February 2005 - 09:36 PM

Let's examine 2.1b with a combination of 2.2a, and 2.2b and/or 1. I say combination, because with higher DNA integrity (through use of method 0), we can allow stem cells to retain their telomerase. Cancer rates will drop. With increased sensitivity to DNA integrity problems (through 2.1b), apoptosis will help reduce cancer rates further by ablating stem cells (and other cells) that are precancerous. Cancer rates will be higher than with WILT, but significantly lower than at present, and increasing abilities to fight cancer will render this even more manageable. Cancer treatment may be expensive, but so will frequent WILT reseedings.

Unfortunately, 2.1b may have the side effect of depleting stem cell reserves, because they will be so active replacing cells that are lost through increased apoptosis. So, 2.2b will serve as a supplementary source of stem cell reserves. Not unlike how the mainstream is viewing the use of stem cells now. But now we've added option 0 (increased DNA integrity) and option 2.1b (increased apoptosis of potentially dangerous cells), so we've reduced cancer rates and many other age-related diseases.

The alternative to 2.2b is 1, allowing us to restore all cells to high DNA integrity, including stem cell reserves. This could even be used in some sort of combination with 2.2b, but the logistics are beyond me at the moment.

How do the two methods compare? de Grey's preferred method, 2.1a with 2.2b, will undoubtedly reduce malignant cancer rates drastically. Using options 0, 2.1b, 2.2a, and 2.2b and/or 1, will not offer as great a reduction in cancer rates. However, cancer rates will still be decidely lower, and treatment options are improving constantly. At some point, the practical concern of availability must be raised. If we have a treatment that reduces malignant cancers 99%, but is only available to 5% of the population, how does this compare to a treatment that "only" reduces cancer rates 80%, but is available to 20% of the population due to reduced cost and frequency? And note, with competition, both procedures would be available, allowing the rich to opt for the "better" treatment, in keeping with the Republican ethic of the mighty dollar.

#5 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 February 2005 - 09:37 PM

Another piece of information is critical to consider, because so far we are addressing DNA damage, cancer rates, etc. in a normal lifespan. With the exponential increase in DNA damage with age, eventually, both methods will fail without replacing a very large percentage of all cells in the body in less than the time that cancers, senescence, etc. set in. This period, depending on body-wide DNA integrity, could be 20-100 years. This makes option 1 attractive, unless we can make 2.2b more robust (this may just be my ignorance, but this is an evolving idea being put forth by an amateur, so I'm depending on the scientists here to improve my idea, not deride it).

de Grey's system will therefore require these boosts to stem cell reserves (i.e. 2.2b) to actually replace all cells in the body, and fairly rapidly given the lack of increased DNA integrity and the lack of decent quality control (with his program, increased apoptosis would actually be a bad thing, since stem cell reserves will have a limited division capacity, so 2.1b is out, and he doesn't have a plan for option 0). Given how often stem cells currently turn over all body tissue, I think he's underestimating the work load on these cells. If they don't replace all cells, and assuming cancerous cells divide to suicide anyway, there is going to be a build-up of senescent and dysfunctional cells, so we won't be in the youthful bodies that many have been hoping for.

But I'd like a second opinion on that last hypothesis of mine, as I'm making assumptions about how much tissue is currently replaced by stem cells in normal people over a period of 10-20 years.

#6 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 February 2005 - 10:07 PM

Keep in mind, our job is to lay out all credible scientific options, regardless of how practical or difficult they will be. Once that is established, then we look at how difficult they will be. But even then, we must still analyze how practical they will be.

WILT is scientifically pretty solid, assuming complete turnover of cells in a reasonable timeframe (less than a lifetime I would venture, perhaps even less than 30-40 years). I'm not talking about the stem cell reserves, I'm talking about all cells, or as near to all as you can get, with the ones not turning over being the lucky few that don't mutate often and divide equally infrequently.

However, issues of difficulty are still to be determined. And more importantly, practical concerns are extremely important in this matter. Financial cost of frequent reseedings, as well as the social risks of programming death unless frequent reseedings are performed, make WILT a less than desireable option. Granted, it's more desireable than aging and death, but not if other options are on the table.

By the way, I do have to point out that combining option 0 (increase DNA integrity) with WILT alleviates some of those concerns. This would increase the time between treatments, reducing both the financial costs and the (serious) risks. But option 0 isn't even on the table in the current incarnation of SENS. As I see it, option 0 benefits de Grey's WILT and the alternative I've laid out (which wasn't my original idea, I'm just trying to give it a fair, layman's terms presentation). It may not be scientifically necessary, but as I see it, it is practically necessary.

#7 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 February 2005 - 10:12 PM

Keep in mind, our job is to lay out all credible scientific options...

I suppose that I should point out that, although I feel it's de Grey's duty to lay out all the options, it's really not. It would help, but it's not his duty. He has laid out a plan with the best of intentions. As a scientist, his role is to lay out what he feels is the best plan and defend it. An argument can be made that part of that process is laying out the competing options, but I don't know that part of scientific etiquette.

As a proponent for policy and funding change, I think it is his duty (to the public, not just to his scientific judgment), but that's also just a matter of opinion on my part.

At any rate, it is the duty of the anti-aging community, and I feel especially the duty of ImmInst. I suppose I should make this clear, as I'm trying to involve de Grey less and less in these discussions, to free up the considerable time of his that we've already taken. If we can make a case to him to amend his website, all the better. If not, we at least need this information available as a resource to ourselves and the scientific community.

#8

  • Lurker
  • 1

Posted 14 February 2005 - 10:45 PM

Okay, option 0 is a red herring: it is not a long-term solution. We'll assume for the moment that achieving zero net DNA damage in each and every one of the hundreds of trillions of cells in the body is virtually (but not absolutely) impossible, and practically impossible given the technology of the next 50—if not 100—years.


Option 0 - Preventing chromosomal mutations is important even if zero net damage is not achieved:

1. old cells - prevents further deterioration. Most notably important in the cells of the brain where we want to keep turnover as low as possible
2. new cells, eg stem cell replenished cells - extends functional lifespan and reduces incidence of disease. More bang for the buck in every stem cell.

as you also noted,

However, as a note of interest, item 0 can decrease the frequency of performing option 1 (and option 2).



#9

  • Lurker
  • 1

Posted 14 February 2005 - 10:50 PM

Financial cost of frequent reseedings, as well as the social risks of programming death unless frequent reseedings are performed, make WILT a less than desireable option.


What an apt description for WILT - programming death.

I disagree with WILT on so many levels. To deliberately impair the innate regenerative capability of a healthy, disease free organism and potentially reduce lifespan by 90% in order to address potential cancer is categorically wrong. It is also scientifically a lazy and non-innovative solution which will never be accepted by the medical community or the public. To test this consider: would you expose your child to a WILT treatment if it were possible or prefer to wait for another solution? I would only recommend a WILT treatment to a person diagnosed with terminal cancer or over the age of 70.

#10 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 February 2005 - 11:13 PM

I would only recommend a WILT treatment to a person diagnosed with terminal cancer or over the age of 70.

I've stated a similar position before.

Consider. If you perform WILT early (age 40, age 20, whatever. Sometime before cancer sets in), then you effectively prevent cancer. At what cost? Remaining lifespan reduced by 50%-80% depending on age of first treatment. Also, frequent reseedings. Etc., etc.

Or, you could perform WILT on someone who already has terminal cancer or is over age 70 (or 85, or 65, some reasonable number picked on roughly 50% likelihood of developing cancer by that age, give or take perhaps 30%).

Cost of waiting? High probability that a cancer will set in for which the WILT treatment will be too late (i.e. the cancer is too far along for the WILT-transfection vector to make a difference, and/or the ALT system will become important).

It's a high cost either way. The "preferable" solution is to perform WILT early, perhaps in the 40's, setting your new expiration date at age 55.

Or, we could proceed with the plan I outlined, 0 and 2.1b, 2.2a, and 2.2b and 1. That is, increase DNA integrity, increase sensitivity to loss of integrity and induce apoptosis. Then, replace cells with existing stem cell lines (not telomerase inhibited). Then, replace stem cell lines with reseeding, and/or reinfect all cells with high fidelity DNA.

Note that the first two steps (0 and 2.1b, followed by 2.2a) can be accomplished in a single application of 1, because 2.2a is an existing systemic strategy. We could even lengthen telomeres, balancing the gains against the increase in cancer rates and cancer growth limits.

Use of option 1: transfection, which requires a technology more comprehensive than today's vectors, as it must reach a very very high percentage of cells. Step 2.2b and/or 1 would then need to be applied at a greatly reduced frequency relative to WILT, perhaps every 40-100 years. Needless to say, nanotech will probably obviate the second treatment, but let's not make that assumption just yet.

#11 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 February 2005 - 11:13 PM

It is also scientifically a lazy and non-innovative solution which will never be accepted by the medical community or the public.

Dr. de Grey's answer to this is that, once the War on Aging is declared, all bets are off on what solutions are acceptable, as long as they work. And it was innovative, in my opinion. Just not practical or remotely desirable, in my opinion.

Dr. de Grey, I hope you don't feel I'm attacking you personally. I have the utmost respect for you and your work. It's just that WILT has never sat well with me, which I'm sure you'll remember from numerous discussions at numerous venues, including at the Fight Aging website. The whole programmed death thing seems like a cop out, an overriding fear of cancer that I think is overstated. Yes, ablation is critical, but there are other ways to achieve ablation, and we don't need to be 100% effective, just effective enough to dramatically reduce the workload on the oncologists. With a reduced workload, and increasing technological savvy, they will be able to manage a moderate cancer workload, making most if not all cancers non-fatal and curable.

WILT is a beautiful attention getter, making a seemingly airtight case that cancer no longer need be a problem. However, I seriously do not see it being the main contender for bringing us to escape velocity. It will be researched, I am sure, and it will probably appeal to a subset of the rich (the ones who don't mind the risk of losing access to WILT treatments for 15 years, as those risks imply that, since they're rich, the world would be pretty screwed as it is, so why risk that against cancer?).

By the way, I am continuing to make assertions based on assumptions that I have laid out here and have not bothered to wait for comment on. Therefore, my argument is one of opinion, based on my above reasoning, which, if validated, would move my argument to one of critical reasoning and not just opinion. Therefore, I await comment on my assumptions of certain scientific principles (e.g. how often stem cells normally replenish every cell in the body, i.e. the systemic turnover).

#12 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 February 2005 - 11:34 PM

Under ablation (2.1), I should add another vague category:
2.1d) Selective signalling to kill certain cell types (cancerous, senescent, etc.) with external factors, e.g. pharmacological or viral.

Examples: A recent finding that re-engineered HIV viruses can be made to target cancer cells.

This would also include recent advances is technology that targets small tumors, using nanotech.

This would of course even include our current chemotherapy.

I view 2.1d as better than 2.1c (which was mostly in jest), but still inferior to 2.1a or 2.1b, and is more a cancer therapy than a cancer prevention. However, supplements and chemicals can also inhibit cancers from forming, whether through actually preventing the switch to a cancerous state, or inducing apoptosis, so 2.1d can be preventive. But I would not view it as a replacement for 2.1b, but it could certainly add to its efficacy. However, as that is a permanent, lifestyle change and treatment, it's not really a procedure that would be included as part of a SENS. In that respect, Dr. de Grey and I agree. I mention it only for comprehensiveness, and so we can eliminate it from further discussion.

Unless, of course, the benefit of such a daily or weekly pharmacological/nutriceutical could rival the benefits of the other 7 aspects of SENS. Which I seriously doubt, and there's little credible evidence of, so we leave those things to LEF, as de Grey suggested. A 20% life extension, which exceeds any credible claims so far from the pharmacological/nutriceutical industry, involving a complete lifestyle change (even if that lifestyle change is as simple as taking your vitamins every day), while impressive and well worth the money for the public, is not an area that we should concern ourselves with. But, enhanced DNA repair and cellular immortality (not to be confused with the systemic immortality we seek), is a worthy goal. In my opinion.

If a pharmacological could add 50%, or 100%, then that's a different story altogether. Until even a remotely credible claim of such is made, 2.1d is safely ignored, I believe.

#13

  • Lurker
  • 1

Posted 15 February 2005 - 03:08 AM

In reference to WILT as an innovative treatment, Jay says:

And it was innovative, in my opinion.


and Aubrey says:

WILT - yes it's an extension of chemo plus bone marrow transplant.


And I say, it has had its dash. The informational landscape has changed since WILT was conceived. We can come up with a better route to dealing with cancer and other inappropriate/dysfunctional cells.

On the other hand, the stem cell seeding component is vital so that should be retained, and expanded on as to implementation, particularly as to getting engrafted stem cells to where they are needed most.

#14 John Schloendorn

  • Guest, Advisor, Guardian
  • 2,542 posts
  • 157
  • Location:Mountain View, CA

Posted 15 February 2005 - 04:43 AM

Jay, I would like to add another variable to your discussion of the function of nuclear mutations with age. Attempting to retro-engineer nuclear damage pathways, one may come up with the following:
Nuchlear DNA damage occurs largely due to reactive oxygen species (ROS). [1]
Mitochondria are a major source of ROS in the cell. [2]
Mutated mitochondria leak more ROS than fully functional ones. [3]
This is the reason a certain part of the rate of nuclear DNA damage is believed to be a function of mitochondrial DNA damage. (Rather than just one of existing nuclear mutations)

Thus, obviating mitochondrial mutations (e.g. via allotopic expression of the 13 genes) is a conceivable way to slow the rate of nuclear DNA damage in its own right.

Prometheus,

I would only recommend a WILT treatment to a person diagnosed with terminal cancer or over the age of 70.

The more successful we are in combating degenerative disease, the more likely we are going to end up being such persons one day. The problem being that in such patients, vector uptake cannot be guaranteed in all cancer cells.

#15 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 August 2006 - 06:20 PM

Given other debates occurring in this forum at the moment, I'm wondering if Dr. de Grey has any comments on this half-baked idea of mine.

Edit: Oh neat, just noticed, 18 months to the day since the last comment on this topic.

#16 ag24

  • Honorary Member, Advisor
  • 320 posts
  • 29
  • Location:Cambridge, UK

Posted 14 August 2006 - 09:12 PM

Indeed, it seems that all prior posts in this thread occurred in the space of just seven hours!

Jay, your line of thought here is not at all half-baked. Your basic point, as I understand it, is that a variety of options exist to lower the cancer rate in the absence of WILT, and these options may be easier to implement (and cheaper once implemented) than WILT itself. I completely agree, and that's why I have always given prominence to promising cancer therapies at the SENS meetings. But I see my role as providing ways to get to escape velocity, and my judgement is that we won't do that by any of these possibly easier measures. I could spend time promoting them too, but that would dilute the WILT message, and thereby delay WILT's arrival. And since WILT is in my view necessary for escape velocity, that would be a retrograde step.

#17 jaydfox

  • Topic Starter
  • Guest
  • 6,214 posts
  • 1
  • Location:Atlanta, Georgia

Posted 14 August 2006 - 11:18 PM

Indeed, it seems that all prior posts in this thread occurred in the space of just seven hours!

In looking back, I see my first five posts span all of two minutes. I apparently must have written all that up in advance, and split it into separate posts for some reason (maybe to make it easier to reference and/or quote).

#18

  • Lurker
  • 1

Posted 16 August 2006 - 08:50 AM

I could spend time promoting them too, but that would dilute the WILT message, and thereby delay WILT's arrival.


God forbid we should delay the arrival of an intervention that cripples every cell in our body, renders us infertile, and condemns us to be completely reliant to a treatment essential for survival with a frequency of administration that may range anywhere between 1 - 10 years! And what is the purpose of such a treatment? To prevent cancer. Not all cancer - since some cancer can propagate without the need of telomerase - but most forms of cancer - hopefully. Of course some people never get cancer - or if they do they don't know about it since their immune system is capable of defeating it. That little fact, however, must be sacrificed on the altar of SENS lest we delay the arrival of WILT.

I have outlined an experiment that can verify whether WILT will work on not with about 3 months of experimental work that most postgraduate biology students should be able to perform.

The WILT proper mouse in the way Aubrey has described it already exists. What Aubrey has not done despite all the bellyaching is design an experiment to see if a stem cell transplant (using telomerase negative stem cells) will rescue the last generation which exibits the majority of telomerase-negative induced pathology. This is a very cheap and simple experiment that someone could do as an honours project (1 year) provided they can get hold of the 5th generation telomerase negative mice. The telomerase negative stem cells could be generated by using an RNAi against hTERT lentiviral construct. Very simple stuff. The only problem I can foresee is in convincing a possible supervisor of the merit of such a project since all it relates to is a proof of concept for WILT.


With the SENS fund sitting nicely at $200K and the above experiment there is nothing that should delay WILT's arrival.. Rejoice..

#19 ag24

  • Honorary Member, Advisor
  • 320 posts
  • 29
  • Location:Cambridge, UK

Posted 16 August 2006 - 11:13 AM

The SENS fund include money that has already been spent as well as money still in the bank.

As I explained earlier, a "stem cell transplant" for a mouse that was suffering pathology in multiple continuously-renewing tissues would have to be a stem cell transplant into all such tissues in order to rescue the mouse comprehensively. A bone marrow transplant would rescue only the blood. It's still a nice experiment though, and of course the RNAi part of your suggestion is unnecessarily complicated as one could just use bone marrow from an early-generation telomerase negative mouse. The main reason the experiment hasn't been done is presumably because the result is so predictable, namely rescue of anaemia but not of non-blood problems. But I'll probably get it done anyway, soon.

#20

  • Lurker
  • 1

Posted 16 August 2006 - 11:59 AM

the RNAi part of your suggestion is unnecessarily complicated as one could just use bone marrow from an early-generation telomerase negative mouse


This is only "unnecessarily complicated" if you have access to the first generation tert -/- mouse as well as G5. Whatever rocks your boat. I was merely trying to make life simpler for you..

#21 marcus

  • Guest
  • 45 posts
  • 0

Posted 14 September 2006 - 10:16 PM

Jadyfox,

I also share some of the same concerns you and others have with WILT. I see WILT as 1 potential(of many) ex-vivo manipulation we can perform on cells if cancer proves to still be able to evade other approaches. It certainly is a potential ultimate cure for cancer, and I don't want to under-estimate cancer's resourcefulness when it comes to evading therapuetic techniques, but WILT is only 1 of many potential ex-vivo manipulation of cells that could lead to better ways to fight cancer.

Let's not forget that WILT will require pretty sophisticated cell therapy to implement and that type of cell therapy alone could drastically lower the incidence of cancer. What do you think the incidence of say lung cancer would be when the majority of cells that compose the tissues of lungs have been replaced by fresh cells that do not carry the baggage of the accumulated nDNA damage that my lung cells now have? I would think it would drop to the level of current 20-30 year olds. While there would still be the unlucky few who acquire the right set of mutations for a cancer to develop, overall the incidence of cancer should fall dramatically simply by replacing the cells with cells whose DNA is pristine. And this could apply to a host of tissues that will have their cells replaced.

This leads to WILT as being a potential therapy for those cancers that although much more rare then today still occasionaly develop. WILT may be an ultimate cure for cancer ever reaching the life threatening stage, but the draw-backs and potential side effects may be more severe then other potential manipulations you could perform on stem/precursor cells prior to implantation that could help the oncologist make cancer a non-issue. I'm not sure I would want to delete an entire gene that could have other functions in regards to maintaining genomic stabiltiy for the benefit of being absolutely sure that cancer doesn't kill me. Although the time scales involved are far from being determined, WILT certainly ups the potential frequency and dependence on cell re-seeding to maintain health. It could be that a better choice would be to have all my cells be more or less like they were when I was 25(telomerase and all) and take my chances that other types of cancer therapies can overcome the gigantic variability in genome expression that cancer has to evade treatment.

I'm going to put together a list of potential other alterations/systems that we may be able to do other then WILT in the next post and I'd appreciate any comment or feedback.

Just as an aside, I am not trying to steer funding away from WILT or attack the idea in anyway. All I am saying is that there may be other alterations we can perform to cells ex-vivo to make them more amenable to cancer treatment that may be good enough to fight what I see as the much rarer incidence of cancer once the type of cell therapy required for WILT is available.

Marcus

Edited by marcus, 14 September 2006 - 10:26 PM.





0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users