[ExI] reverse aging

[The Avantguardian]

----- Original Message ----
> From: Ben Zaiboc <bbenzai at yahoo.com>
> To: extropy-chat at lists.extropy.org
> Sent: Wed, December 1, 2010 5:17:38 AM
> Subject: Re: [ExI] reverse aging
> 
> Interestingly, Aubrey de Grey's SENS includes a scheme for totally eliminating 


>all cancers, by taking the opposite approach:  Get rid of telomerase and all 
>other means of lengthening telomeres.  Of course, that brings its own problems, 


>but it stops cancer dead in its tracks.

When I first read this, I thought it was very naive. So I looked up a detailed 
description of his strategy here:

http://www.sens.org/files/pdf/WILT.pdf
 
My objections to it follow:
 
1. First what he was suggesting was similar to purposefully giving people the 
equivalent of dyskeratosis congenita, a genetic birth defect where people are 
born without normal telomerase function. The problem is that these people are 
actually *more* prone to cancer and start getting them around ten years old. You 

can find a complete medical description of dyskeratosis here on pubmed for free:

http://www.ncbi.nlm.nih.gov/pubmed/20301779
 
 
2. The second reason is that once a cell violates its genetic programming and 
goes cancerous, all the rules go out the window. If telomerase is available, it 
will use it to lengthen its telomeres. If telomerase is not available it will 
start using alternative 

methods to lengthen its telomeres like using the homologous recombination 
machinery 

normally reserved for DNA repair and meiosis of germline cells.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2892175/
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2649016/?tool=pubmed
 
And if that doesn't work, cancer cells have no qualms against just sticking 
chromosomes together end to end with non-homologous end joining. Cancer cells 
will duplicate genes or entire chromosomes (polyploidy), lose genes or entire 
chromosomes, and mix bits and pieces of different chromosomes together if need 
be.

http://www.nature.com/onc/journal/v21/n45/pdf/1205566a.pdf 
 
So profound is a cancer cell's ability to mutate at fast speed that it can form 
structures known as ring chromosomes that recapitulate the ancestral bacterium's 

circular telomere-independent chromosome.
http://atlasgeneticsoncology.org/Deep/RingChromosID20030.html

In short, cancer cells have all the tools of evolution at their disposal at 
speeds normally associated single-celled organisms.
 
 
3. The next problem is that de Grey's strategy underestimates the importance 
of the immune system in cancer prevention. This process is called 
immunosurveillance and mice and people with defective immune systems are 
notoriously prone to cancer.  The white blood cells that normally protect people 

from cancer *need* telomerase to function properly because the mechanism by 
which they operate depends on the mass replication of the white blood cell 
lineages that can recognize and kill tumor cells.
 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1857231/
 
Of course this mechanism of amplification of the efficacious clones is used to 
combat mundane infections as well. So not only would telomerase-deficiency make 
one prone to cancer, it would make one susceptible to death from normally benign 

viral, bacterial, and fungal infections. 
 
4. De Grey's solution to this problem is "reseeding" whereby engineered stem 
cells are periodically given to people to replace high turnover tissues such as 
the blood cells, skin, and gut epithelium. This work-around however brings 
up the next problem: The relationship between cancer and stem cells is 
poorly understood and these reseeded stem cells could very well *become* 
 cancer.

http://www.ncbi.nlm.nih.gov/pubmed/20688584
http://www.ncbi.nlm.nih.gov/pubmed/19684619
 
And if the stem cells are treated to lack telomerase, like the rest of the cells 

of the body in WILT, they no longer qualify as stem cells since the capacity for 

self-renewal is one of the defining characteristics for stem cells. So these 
telomerase deficient stem cells would be the medical equivalent of GM food crops 

that can't make seeds, requiring one to be beholden to whatever biotech company 
happens to be manufacturing your crippled stem cells for you. If we are talking 
about 

immune system stem cells, then catching a simple cold could deplete ones entire 
resevoir of non-self-renewing hematopietic stem cells.    
 
5. Aside from the theoretical problems with the WILT strategy, the technical 
challenges would be horrendous. With the current state of the art, gene 
knockouts are a messy and rather hit or miss affair. They involve trying the 
targeted gene deletion on a great many embryos, then screening for that one 
precious embryo or cell line in which it worked. While this is feasible with 
mice, the bioethicists would have a canniption if you tried that with human 
embryos. But what use is a gene knockout of an embryo going to be to an already 
full grown population of possible cancer victims? While gene knockouts are done 
routinely on human cells in a petri dish, I am not aware of any existing 
technique that would allow one to delete a gene from all 10^14 cells of an adult 

human in vivo:
 
http://www.biotechniques.com/BiotechniquesJournal/2006/September/Simple-one-week-method-to-construct-gene-targeting-vectors-application-to-production-of-human-knockout-cell-lines/biotechniques-40137.html?pageNum=3


 
So my final analysis is that de Grey's strategy is inelegant, convoluted, and 
unlikely to work in a time and cost frame that would make it competitive with 
other developing cancer treatments. Top-down management seldom works in 
bottom-up organized systems. Such seems to be as true in biology as it is in 
economics.  
 
From: Adrian Tymes <atymes at gmail.com>
>To: ExI chat list <extropy-chat at lists.extropy.org>
>Sent: Wed, December 1, 2010 9:26:33 AM
>Subject: Re: [ExI] reverse aging

>What if you extended the telomeres, such that the only way senescence would
>set in is via damage leading to cancer?
 
In theory, this could work but there are several very serious technical 
challenges involved.
 
  Maybe add in a very slow telomere
>extending enzyme, that replaces telomeres fast enough for normal cell division 
>(to
>replace worn out cells) but can't keep up - or even goes into reverse - if very 


> rapid
>cell division is encountered (such as in cancer).  Might that work?

The main technical challenges would be coming up with a molecular design 
for your custom enzyme and then getting it into all the cells of the adult 
human, without disrupting any important housekeeping genes.
 
Since using protein folding at home, super computers, and other brute force 
methods give limited results on predicting the structure of existing proteins 
from their sequence data, it would be even more of a pain to design a 
novel enzyme to fold and function the way you would like. Especially because you 

would need to figure out how to regulate its function based on the pace of cell 
division as 

you envision it.

Then, even if you had this fantastic new enzyme, how would you deliver it to all 


the 10^14 cells in an adult? Most gene therapy vectors can only target a 
single cell type. Now you could transfect your custom enzyme gene into human 
embryos and create a race of transgenic humans but that doesn't do your average 
babyboomer any good.
 
Now I am not trying to discourage anyone here, but bioengineering humans to live 


longer is not going to a quick fix. Part of the problem is that human cells 
evolved to replicate like crazy in the first 20 or so years of life allowing for 

a single-celled embryo to become an adult human and then suddenly cut back to 
the considerably slower levels of cell replication required for homeostatic 
maintenance for the remaining 60 years.
 
Despite this fact, when high-turnover tissues are considered, approximately 75% 
of these cell divisions happen after maturity. So any intervention to completely 

halt cell division in order to prevent cancer will likely end up being worse 
than the disease.
 
 
Stuart LaForge 

"There is nothing wrong with America that faith, love of freedom, intelligence, 
and energy of her citizens cannot cure."- Dwight D. Eisenhower