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Let's imagine that we understood DNA programming and our genome very well and realized that there were some significant flaws (we die, we need sleep, etc.) And let's imagine that we understand how to make our genome do what we want, but it's a major refactor. We're going to have adjust 10-15% of our DNA. (Note this is just a contrived example to suggest why we would want to make such a drastic change - our ability to actually know what changes to make is unimportant for the question.)

How would we replace/or modify this much of our DNA? It seems the problem is very similar to gene therapy, but on a larger scale.

A few possibilities come to mind. We could make a virus that would modify our DNA. Or perhaps we could generate the new genome and inject it into some cells which would then just outlive the others (eg because these cells won't have a Hayflick limit) or will be able to generate lots of new adult stems cells with the "refactored" DNA?

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  • $\begingroup$ I don't think replacing that much DNA would be possible in anything larger than a zygote. $\endgroup$ – user137 Mar 12 '15 at 0:56
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    $\begingroup$ Why is this opinion based? It's not a question like "what is your favorite codon". I'm asking a serious question about the ability to replace DNA in a complex organism. $\endgroup$ – Yehosef Mar 12 '15 at 7:27
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    $\begingroup$ Any statement of the form "Is X possible" where X is a completely speculative and untested concept is opinion-based here. $\endgroup$ – March Ho Mar 12 '15 at 8:17
  • $\begingroup$ @MarchHo - I reworded the question. I fully expect that an approach is possible, eventually. I just don't know what approach would work. I suggest two. Perhaps the virus approach is untenable because virii are small and replacing that much DNA would not be possible even with a complex DNA. en.wikipedia.org/wiki/Gene_therapy is basically this same concept at a much smaller level. $\endgroup$ – Yehosef Mar 12 '15 at 8:49
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    $\begingroup$ I think the bigger problem is replacing the DNA in every cell of an adult. Gene therapy will probably be most successful in cases were you only need to deliver a small amount of DNA to a certain set of cells. There are enough problems getting a 5000 bp plasmid into tissues, trying to get entire chromosomes into cells would be much harder. $\endgroup$ – user137 Mar 12 '15 at 14:08
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Let's imagine that we understood DNA programming and our genome very well and >realized that there were some significant flaws (we die, we need sleep, etc.) And >let's imagine that we understand how to make our genome do what we want, but it's a >major refactor. We're going to have adjust 10-15% of our DNA.

I think we both recognise that this is a very naive view of biology and the nature of how organismal properties emerge (through multiple levels of systems) ultimately from the genetic code, the information in the genome, and the developmental process.

It is more pertinent and promising to think about treating genetic diseases.

Some genetic diseases are caused by mutations to single basepairs (e.g. the HgbS variant of the haemoglobin beta chain, which causes sickle-cell anaemia). Other genetic diseases are caused by rearrangements of large segments of chromosomes, and the gene dosage imbalances that arise from this (e.g. Charcot-Marie-Tooth syndrome 1A). Finally, some genetic diseases are caused by a major gene-dosage imbalance caused by having an unusual set of chromosomes, "aneuploidy" (e.g. down syndrome, where chromosome 21 is present in 3 copies).

'Large-scale' gene therapy could be something useful for aneuploidy. Recently, the mechanism for inactivating one X-chromosome in female somatic cells has been applied to silencing the surplus chromosome 21 of Down Syndrome.

In yeast, a 'designer chromosome' has been chemically synthesised, and has been used to replace the corresponding native chromosome in yeast cells.

So although I think the premise of your question is basically science-fiction and naive, it is becoming possible to silence or replace whole chromosomes. More realistically than making our species immortal and ever-awake, this technology could possibly translate to therapies for some genetic diseases. But of course, the problem of retrospectively getting your therapy in to many somatic cells is still there. Engineering zygotes is feasible but has ethical problems - also, where pre-implantation screening is permitted, IVF can simply include genetic selection rather than genetic engineering!

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    $\begingroup$ Thanks for the answer! I don't recognize it as a naive view of biology b/c I really know very little about biology. But I understand computers and programming and my understanding of DNA/biology is that they are very complex biological machines/computers. Even though our understanding of these mechanisms is only in its infancy, I don't see any reason we won't eventually understand it at a level that we can program whatever we want (see en.wikipedia.org/wiki/Synthetic_biology) Maybe that's naive - but I'm not convinced. $\endgroup$ – Yehosef Mar 12 '15 at 16:02
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    $\begingroup$ The problem is that the kinds of properties of living things you can readily see and care about (you list needing to sleep, mortality - these are especially tough cookies!) are emergent, and very far abstracted from the genetic information. Abstracted through multiple layers of extremely complex non-linear dynamic systems, such as genetic regulation, patterning in development, tissue interactions. Also, these properties have emerged from evolution by natural selection, and this 'blind' optimisation process often leads species down dead-ends, often compensating its past wild excursions... $\endgroup$ – Teige Mar 13 '15 at 17:50
  • $\begingroup$ Evolution by natural selection doesn't have foresight, and so while it is busy selecting 'fit' individuals under the circumstances du jour, over long time-spans it can be raising dependencies and fragilities. The panda bear is a great example, along with the swathes of extinct forms. Maybe for a computer scientist you could think about digging down into treacherous local minima...? But your question is a super-interesting one, and it turns out people are working both on replacing large chunks, and replacing all instances of a short 'word'. $\endgroup$ – Teige Mar 13 '15 at 17:54
  • $\begingroup$ I understand that it's not always as simple as finding the "need sleep" gene. Genes cause proteins which cause lots of interesting thing. But I expect that within the next few hundred years (at least) the growth of our understanding of biology combined with growth in computer simulations/modeling will provide us with tools far beyond our ability to even grasp them today. We have computers today which are creating simulation of the formation of the universe - how many more years before we have reasonably accurate models of human biological systems? I don't expect that many. $\endgroup$ – Yehosef Mar 14 '15 at 21:49
  • $\begingroup$ Yeah the future is exciting, let's hope we live long enough to see some interesting stuff. We're currently at the stage where (rather) small proteins and some solvent can be simulated as a system of atoms under relevant physical forces, for long enough for the protein to fold up in to a reasonable structure. But this is the top of the top and isn't really giving an insight in to biology yet (it will!!) Meanwhile we're trying to predict folded protein structures from sequence data as a short-cut. It's slow progress.... $\endgroup$ – Teige Mar 16 '15 at 17:13
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A major drawback and problem with your idea is that some genetic problems are developmental and have no effect if applied on adults. For example, a gene known to cause crooked teeth would have to be fixed before permanent teeth grow in - no point in patching it after that, except if you also want to patch in infinite tooth replacement.

Retroactively fixing developmental problems through DNA is a pain. In the worst case, you have to clear out the defective piece, then regenerate it after the patch. Bioactive machine parts or cybernetics might be preferable. If you have the tech to fix DNA like that, you probably have the means to produce the needed machine parts.

"Modifying the DNA" isn't a magic solution either. There are all sorts of ways that genes can be deactivated or suppressed - and there's a field of study around such mechanisms known as epigenetics. You could waste billions on patching a gene only to find that your patch has no effect because you failed to consider these.

The most promising applications of gene treatments for adults are mainly in cases where a faulty gene generates a malfunctioning product that is normally constantly needed. An example is genetic insulin deficiency (where a person is unable to produce insulin, effectively causing diabetes.) If the gene is corrected, insulin can be properly produced.

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