Is gene replacement a practical way to fix random mutations?

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Recently I asked if prime editing can be used to reverse the random mutations we accumulate with aging(https://www.physicsforums.com/threa...ry-harmful-mutation-in-all-our-cells.1003279/) but now I have a different question. Can we simply replace our genes to get rid of random mutations we accumulate with age?. I read about gene replacement but I still don't get what happens to the original gene that is being replaced, is it being removed from the cell or just being ignored?. What are the limitations of gene replacement? is it possible to replace all of our genes with copies of our genes that are free of mutations?.
Is it possible to completely remove mutated gene from the cell?.
 

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  • #2
jim mcnamara
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In theory the short answer is "a very limited maybe" on a case by case basis depending on where the gene is turned on. Brain tissue would be off limits, for example

Plus:
I think you may have an assumption that gene editing works on whole tissues or organs like the liver, heat, or gastric epithelium.

Edits are made using tissue culture in the lab, right? The edited cells could be injected into an organ (I am guessing). Then what? If you mean stem cells -- that may in theory have some traction for ultimately changing an actively dividing tissue like epithelium in your gut. This is because in this case the stem cells make epithelial cells on the fly.

But what happens to the millions of existing cells with "bad" DNA in the organ? You cannot suck them out, edit them, then replace the whole organ or tissue. Think of what this means to an organ like the brain made of complex neurons that over a lifetime have made synaptic interconnections (memories, etc). What you would need to do is have surgical replacement of entire organs remade from scratch with "good" DNA. Not impossible.

Ageing causes the ends of chromosomes - telomeres - through repeated cell divisions to become shortened. This causes problems in cell division. This is not necessarily bad DNA, just a worn out "package". I do not know if DNA editing could be used to repair telomeres in active cells.

FWIW
Environmental exposure is a primary driver for damaging DNA, example smoking or living with a smoker.
Therefor, DNA problems you fix have the potential get undone pretty quickly. Bladder cancer has prevalence in anyone who has smoked at all or is now smoking.

Strong association:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441175/
Previous studies indicate that the population attributable risk of bladder cancer for tobacco smoking is 50–65% in men and 20–30% in women and that current cigarette smoking triples bladder cancer risk relative to never smoking. Over the last 30 years, incidence rates have remained stable in the United States (men: 123.8/100,000 person-years to 142.2/100,000 person-years; women: 32.5/100,000 person-years to 33.2/100,000 person-years), yet changing smoking prevalence and cigarette composition warrant revisiting risk estimates for smoking and bladder cancer in more recent data.

Applying this example to your question would mean that it seems reasonable to assume that DNA in a smoker is a mess. So what do we do?
 
  • #3
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In theory the short answer is "a very limited maybe" on a case by case basis depending on where the gene is turned on. Brain tissue would be off limits, for example

Plus:
I think you may have an assumption that gene editing works on whole tissues or organs like the liver, heat, or gastric epithelium.

Edits are made using tissue culture in the lab, right? The edited cells could be injected into an organ (I am guessing). Then what? If you mean stem cells -- that may in theory have some traction for ultimately changing an actively dividing tissue like epithelium in your gut. This is because in this case the stem cells make epithelial cells on the fly.

But what happens to the millions of existing cells with "bad" DNA in the organ? You cannot suck them out, edit them, then replace the whole organ or tissue. Think of what this means to an organ like the brain made of complex neurons that over a lifetime have made synaptic interconnections (memories, etc). What you would need to do is have surgical replacement of entire organs remade from scratch with "good" DNA. Not impossible.

Ageing causes the ends of chromosomes - telomeres - through repeated cell divisions to become shortened. This causes problems in cell division. This is not necessarily bad DNA, just a worn out "package". I do not know if DNA editing could be used to repair telomeres in active cells.

FWIW
Environmental exposure is a primary driver for damaging DNA, example smoking or living with a smoker.
Therefor, DNA problems you fix have the potential get undone pretty quickly. Bladder cancer has prevalence in anyone who has smoked at all or is now smoking.

Strong association:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3441175/


Applying this example to your question would mean that it seems reasonable to assume that DNA in a smoker is a mess. So what do we do?
I not sure I understand your answer, why the brain should be off limits?. can't we replace or provide genes to an existing cells in the body without getting them out?.
I don't talk about what is possible right now but what is possible and practical using gene replacement therapy with delivery methods that will allow us to deliver gene therapy in-vivo to the brain. From my searching in google it looks like there some progress in using gene editing on the brain in-vivo.
 
  • #4
phyzguy
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How exactly would you propose to remove the genetic material from the trillions of cells in your body and replace it with something else?
 
  • #5
jim mcnamara
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Based on your question I see that you think this is like walking some kind of machine and getting whole body DNA repaired. Not in the foreseeable future. The only way to get new DNA in a cell is to replace that cell with new cell with new DNA. This requires killing the starting cell. -- none of this really possible now.

You cannot go into an organ and edit DNA inside the cells in place while they are still alive - inside the brain or whatever organ. You do realize that the average human brain has a LOT of cells, called neurons

86 billion neurons:
https://www.nature.com/scitable/blog/brain-metrics/are_there_really_as_many/

Approximately the same as the number of stars in the Milky Way Galaxy per article.

I mention the huge number simply to show that it makes sense to edit genes before they are implanted in a human egg cell. Before birth, before there are too many cells to deal with.

Any answer beyond that is really pushing too far into Science Fiction - what could we do 100 years from now?
 
Last edited:
  • #6
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Based on your question I see that you think this is like walking some kind of machine and getting whole body DNA repaired. Not in the foreseeable future. The only way to get new DNA in a cell is to replace that cell with new cell with new DNA. This requires killing the starting cell. -- none of this really possible now.

You cannot go into an organ and edit DNA inside the cells in place while they are still alive - inside the brain or whatever organ. You do realize that the average human brain has a LOT of cells, called neurons

86 billion neurons:
https://www.nature.com/scitable/blog/brain-metrics/are_there_really_as_many/

Approximately the same as the number of stars in the Milky Way Galaxy per article.

I mention the huge number simply to show that it makes sense to edit genes before they are implanted in a human egg cell. Before birth, before there are too many cells to deal with.

Any answer beyond that is really pushing too far into Science Fiction - what could we do 100 years from now?
But what with all the studies about gene editing? there are many studies about in-vitro and in-vivo cases of gene editing and there are even approved drugs that deliver new genes to cells like Zolgensma. so what do you mean when you say "The only way to get new DNA in a cell is to replace that cell with new cell with new DNA. This requires killing the starting cell. -- none of this really possible now"?.
 
  • #7
phyzguy
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But what with all the studies about gene editing? there are many studies about in-vitro and in-vivo cases of gene editing and there are even approved drugs that deliver new genes to cells like Zolgensma. so what do you mean when you say "The only way to get new DNA in a cell is to replace that cell with new cell with new DNA. This requires killing the starting cell. -- none of this really possible now"?.
Delivering a new gene is one thing. You simply add this genetic material to what is already there. This is very different from your OP, which asked about removing and replacing the existing genetic material.
 
  • #8
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Delivering a new gene is one thing. You simply add this genetic material to what is already there. This is very different from your OP, which asked about removing and replacing the existing genetic material.
it was one of my questions, but the main question was about fixing mutations(the damage they cause) by using gene replacement which is according to sciencedirect website: "Gene replacement therapy is the technique of recognizing a faulty gene, applying a piece of DNA in its correct form though a viral vector (known as the carrier molecule) to the gene, thus overriding the identified faulty gene with the correct copy."
that why I asked if the original gene is being ignored or removed.
 
  • #9
jim mcnamara
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@Ygggdrasil understands the ins and out of this question. I do not know if gene replacement therapy is widely used or even used in the sense you mean. You can temporarily override existing mRNA by introducing new mRNA. For example viruses co-opt cell mRNA machinery to make new viruses. Some viruses also co-opt
DNA. Retroviruses actually insert viral DNA into human DNA, about 8% of our existing human DNA comes from that activity in the deep past.

https://en.wikipedia.org/wiki/Retrovirus

None of this is editing as far as I can tell. Especially in the sense you mean: erase one gene, replace it exactly - in all cells in humans
 
  • #10
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@Ygggdrasil understands the ins and out of this question. I do not know if gene replacement therapy is widely used or even used in the sense you mean. You can temporarily override existing mRNA by introducing new mRNA. For example viruses co-opt cell mRNA machinery to make new viruses. Some viruses also co-opt
DNA. Retroviruses actually insert viral DNA into human DNA, about 8% of our existing human DNA comes from that activity in the deep past.

https://en.wikipedia.org/wiki/Retrovirus

None of this is editing as far as I can tell. Especially in the sense you mean: erase one gene, replace it exactly - in all cells in humans
But gene editing is possible today right? we have things like CRISPR gene editing and prime editing that can actually change our genome and CRISPR is even being tried on people in clinical trials to remove mutations from the body. Can CRISPR replace genes or just fix single mutations?.
 
  • #11
Chromosome Replacement Therapy is what you are looking for. It is possible, but pretty bleeding edge technology and not proven out in humans really at all.
 

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