5 replies to this topic

[Cyto]

Mmmmm, something to keep in mind.

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Gene defect linked to premature aging

Johns Hopkins Kimmel Cancer Center researchers have identified a gene that, when altered makes cells and animals age prematurely and die. The findings, reported in the May 1 edition of Genes and Development, may provide a new target for therapies that force cancer cells to an early death.
The gene, called PASG (Proliferation Associated SNF2-like Gene), normally works by decreasing the activity of other genes in two different ways: helping to add chemical groups to DNA, in a process known as methylation, or by modifying protein structures called histones that help wind DNA into compact coils.

"In order to grow and stay alive, cells depend on the PASG gene to reduce the activity of other genes, but it's a very complicated process - much like modifying the engine of an F-15 fighter jet while it's flying," says Robert Arceci, M.D., Ph.D., King Fahd Professor and Director of Pediatric Oncology, and director of the study.

The Hopkins team began investigating the PASG gene after finding that its activity is integrally involved in cell growth and mutated forms of the gene occur in acute leukemias. Using genetically engineered mice, Arceci's team knocked out part of the "core engine" of the PASG gene, decreasing methylation throughout the genome and allowing the wrong genes, particularly those associated with premature aging, to be active all the time. The result was that mice with this mutated PASG protein showed signs of premature aging and profound growth problems, including low birth-weight, graying and loss of hair, skeletal abnormalities, reduced fat and early death.

"To keep body tissues working correctly, the PASG gene appears to help cells regenerate, mature and prevent early aging," explains Arceci. "Each cell is programmed with a set number of replications before it dies. With a mutated PASG gene, the cell may replicate only a fraction of the time, and then it dies prematurely," explains Arceci.

[manofsan]

Hmm, well imagine if we were talking about an automobile.

"Engineers have located a car part which, if removed, will prevent your car from running"

Well, that could apply to a whole lot of car parts. Similarly, I'd imagine that with the genome, you need a whole lot of genes to be working properly and in synchronized harmony to keep things healthy and happy. Any one of them failing can screw up the entire works.

Aging is a very vague thing to identify. Any number of genetic pathologies could resemble natural aging, I'd think. So I'd say that there's no one magic gene that will help us to cure aging, but rather a whole bunch of genes and their precisely choreographed settings which would help this. I'd imagine that deriving a genetic cure for aging could potentially be as complex as genetically engineering a whole genome from scratch.

[Cyto]

Ok manofsan lets figure this out.

What would need to happen for a 'theory of continual cell existance' to work in a feasable manner?

We can record gene sequences but epigenetic factors such as cell memory modules (CMMs) are a problem. SO, if we were to introduce a designed chromosome with 'like-sequences' the epigenetic response could be to make the endogenous state reflect on the newly introduced chromosome. I could imagine the first step of this to be using a key gene already present in the hCell, make it into a proximal ring that is accepted as apart of the chromosome like in some virions, and see if proteins are placed.

As for the 'old' chromosomes, that will require further understanding of specific fragmentation mechanisms...could we make a chromosome predatory against specific other ones?

Surely we can't solve it all from here but what are we without ideas right?

[manofsan]

Hmm, interesting conjectures...

Well, even if we can't make the new chromosome itself predatory against an existing target chromosome, we could use some kind of chromosomal delivery agent that would incorporate agents to destroy the old chromosome.

So imagine some artificial chromosome being created in bulk in vitro, and being packaged into some kind of delivery liposome along with some chromosome-specific anti-bodies that would be explicitily designed to knock out the old chromosome. The liposomes are introduced to the body and penetrate into cells, simultaneously releasing their replacement chromosomes and also the knockout anti-bodies.

Or alternatively, perhaps the artificial chromosome itself would itself including gene-coding that would generate knockout agents that specifically target the old chromosome. Perhaps that might be even better, because you want to ensure that the successful introduction of the new chromosome is completely correlated with the knockout of the old one. Because you don't want your new chromosome having to coexist with and compete with that old one expression-wise, nor do you wish to see that old chromosome knocked out without the replacement being there to take over.

And yet there's still the mosaicism danger, where some cells successfully receive the chromosome substitution, while others do not. As others here have previously commented, you'd need a highly aggressive promoter, because you have to get each and every last cell. I would recommend coupling your highly aggressive promoter with a highly aggressive lysing/apoptosis agent to eliminate the unreformed cells. There needs to be a focused effort to address the challenges of how to successfully completely modify a large cell population.

The knowledge of the factors governing the methylation (epigenetic "bit states") seems to be in its infancy, and yet this seems very important for "imprinting" purposes, to get the DNA to function properly.

[manofsan]

Hmm, or what about designing a chromosome-substitution agent that replicates itself viral-style, but only for a finite number of generations? Perhaps this could be done telomere-style or perhaps through another method.

You would initially manufacture it in vitro and introduce it into the body, where it would successfully penetrate some cells and substitute the new chromosome. Encoded onto the new chromosome would be the instructions to generate copies of the chromosome and its delivery agent, as well as perhaps generating apoptotic agents to lyse the old cells.

That way, the successfully altered cells would themselves be constantly promoting transformation of the remaining unaltered population, and even the removal of the unaltered cells. Like I said before, the best tissues to initially target would be the immune system, since it despatches mobile cells to go after the rest of the body.

You either want to have some kind of time-to-live limiter which only allows your agents to function for a finite number of generations, or else perhaps your substitution agents should only be allowed to function in the presence of a certain substance. You take a particular drug or substance during the substitution period, and then afterwards when your body's genome is sufficiently transformed you stop taking it, and the chromosome substitution activity ceases.

Perhaps the genetic coding would be custom-designed according to the specifics of our existing personal genome for each of us.

It's interesting to think about genetic tools which can be equated to logic operations
(eg. loops, conditional or comparison switches, etc) because what we are talking about is programming, here. In computer programming, we are able to express our agenda in higher level statements, which are then compiled into the machine language in which the machine operates. It would be great to have a similar compiler that could allow us to express ourselves in a higher-level logical language, and have this translated into the genetic code that our cellular machinery understands.

Perhaps the higher-level language could be so high-level so as to permit us to articulate purely in terms of macroscopic bodily measurements and higher-level environmental parameters, and the compiler would intelligently compile this into the genetic code, like an expert-system, taking into account the specifics of our existing personal genomic information.

This would be an interesting and marvelous challenge, to bring transgenics to the mass market. What do you think?

[Cyto]

Mep, sorry for missing this one manofsan. Give me a day or two so I clear my head some.