3 ms·

Maybe because chemo currently gives you 10% chance, while gene editing at the whole embryo level has 100% chance of resulting in mosaicism. This more recent wo

by Amygaz 9y ago

Maybe because chemo currently gives you 10% chance, while gene editing at the whole embryo level has 100% chance of resulting in mosaicism. This more recent work by Mitalipov's group dealt with single cell embryo and still ended up with mosaicism, which I was a bit surprised at first. But when you think about it, this single-cell embryo's genome is actively being replicated, so not 100% of the alleles will be edited. A way around it, would be to reactivate Cas9 after every cell division event, or maybe applying Cas9 gene-drive to embryo development. Also, I have yet to see a CRISPR paper with ensemble sequencing showing no off-targets. Even all the enhanced specificity Cas9 variants had a small percentage of off-targets.

AstralStorm 9y ago
And is mosaicism inherently bad or harmful? Some people have more than one genome and don't even know about it... Many of the worst disorders are lack of function mutations where mosaicism would indeed fix it. I would be more worried about unwanted edits than missing ones.
- Amygaz 9y ago
  Mosaicism is not inherently bad. It is definitely case specific. The current technology just doesn't allow much control over how much mosaicism you will get, on top of the off-targets, which is your point basically. The same mosaicism phenomenon which cause tabby cat's coat (especially callico) can be seen in human and would cause that individual to sweat by plaques, instead of the entire body. So you could imagine a scenario where someone would like to select a specific eye, or hair, or skin pigmentation, and end up with inequal pigmentations or a patchwork. That actually sounds cool... In the case of an autoimmune disorder, like type-I diabetes or a blood disorders like beta-thalassemia, you would absolutely need to hit the proper germline which is responsible for creating your diseased cells. So that's a hit or miss, there is no inbetween. If you do have a hit, then while this germline is dividing and differentiating, it would need to reach a threshold at which the disease becomes asymptomatic. I don't what that number is for any of two diseases I just mentioned, but I would think it is higher than 50% of your cells that need to be corrected, so you would need to successfully hit more than one allele in your succesfully hit germline population that will become blood making cells. It's a lot of moving parts, which needs to align correctly. That being said, I am optimistic that we will eventually get there. I have some doubt about the scientific pertinence of that "breaking news", i.e. I just don't believe they have accomplished anything that wasn't obvious, but being an optimist, I am sure that not all the ink will be a waste. Nice question.
deleted 9y ago
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by Amygaz 9y ago

AstralStorm 9y ago

And is mosaicism inherently bad or harmful? Some people have more than one genome and don't even know about it... Many of the worst disorders are lack of function mutations where mosaicism would indeed fix it. I would be more worried about unwanted edits than missing ones.

Amygaz 9y ago
Mosaicism is not inherently bad. It is definitely case specific. The current technology just doesn't allow much control over how much mosaicism you will get, on top of the off-targets, which is your point basically. The same mosaicism phenomenon which cause tabby cat's coat (especially callico) can be seen in human and would cause that individual to sweat by plaques, instead of the entire body. So you could imagine a scenario where someone would like to select a specific eye, or hair, or skin pigmentation, and end up with inequal pigmentations or a patchwork. That actually sounds cool... In the case of an autoimmune disorder, like type-I diabetes or a blood disorders like beta-thalassemia, you would absolutely need to hit the proper germline which is responsible for creating your diseased cells. So that's a hit or miss, there is no inbetween. If you do have a hit, then while this germline is dividing and differentiating, it would need to reach a threshold at which the disease becomes asymptomatic. I don't what that number is for any of two diseases I just mentioned, but I would think it is higher than 50% of your cells that need to be corrected, so you would need to successfully hit more than one allele in your succesfully hit germline population that will become blood making cells. It's a lot of moving parts, which needs to align correctly. That being said, I am optimistic that we will eventually get there. I have some doubt about the scientific pertinence of that "breaking news", i.e. I just don't believe they have accomplished anything that wasn't obvious, but being an optimist, I am sure that not all the ink will be a waste. Nice question.

deleted 9y ago

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