Submitted by scrooch t3_xzfe6h in askscience
I'm interested to know what sort of assumptions are built into DNA about the structure of the cell and if there are differences in mammal cells beyond DNA. I know there must be some differences since mitochondrial DNA will be different in a mouse vs human, but does it actually interfere with the ability to function with human DNA?
Not to mention the relative expression of these new proteins would likely be off compared to those in a normal human cell. Having the new DNA is one thing, but having the correct epigenetic factors governing gene expression is another issue.
To be fair, CRISPR can also be used for epigenetic editing. But doing that across, if not the entire genome then at least all of the genes, is... a challenge.
>If we presume that you could wave a wand and change the DNA using CRISPR all at once
If you wanted to just swap out one cell's genome for another, you could just physically remove and replace the nucleus, which has been used to clone mammalian cells. It's usually done with an oocyte and somatic nucleus from the same species, but it is apparently possible to create a viable embryo with a fusion of cellular material from two closely-related species, as was done with domesticated cows and Bos gaurus. (Linked paper is referenced here on Wikipedia)
While I obviously can't say for sure without empirical evidence, I'm quite confident that the mouse oocyte proteome is different enough from a human one that gene transcription would not be properly induced to create a human stem cell.
Finally, chromosomal structure and epigenetic modifications haven't been mentioned here. CRISPR/Cas9 gene editing doesn't provide the tools to restructure chromosomes, either in terms of the grouping of DNA into chromosomes or the packing of DNA into chromatin, nor does any other technology I'm aware of. I'm sure some researchers have been able to induce particular chromatin modifications, but much of how epigenetic regulation works remains unknown.
> > > > > Finally, chromosomal structure and epigenetic modifications haven't been mentioned here. CRISPR/Cas9 gene editing doesn't provide the tools to restructure chromosomes, either in terms of the grouping of DNA into chromosomes or the packing of DNA into chromatin, nor does any other technology I'm aware of. I'm sure some researchers have been able to induce particular chromatin modifications, but much of how epigenetic regulation works remains unknown.
dCas9 (or other Cas proteins) can be fused to a variety of chromatin modifying factors, so epigenetic editing is entirely possible. But good luck doing that across the entire genome in a single cell.
Ah okay, proteins are the thing I was missing. If you forgive the analogy, it's like taking a running computer and switching out the code that is running, the information in RAM (the proteins) used to communicate with the other devices (organelles) will not match.
It's this difference in the protein protocol between the nucleus and the organelles that probably causes viruses to work in some species and not others? Thus there's probably evolutionary pressure to diversify that protocol.
Taking another wild leap, humans could potentially modify that protocol in such a way that humans look exactly the same but would be resistant to cross species viruses.
Yes, the computer analogy is pretty good, but the proteins can be for signaling, enzymes, or other purposes..
Can the old co-exist with the new? Thats a question i have no idea about (I will be honest)
There are a few reasons why viruses from other species can't infect human cells (or well) generally it's a matter of the virus gaining entry to the cell to hijack cellular machinery (i will admit, it's been a few years since my virology courses) so physically differences at this stage generally prevents entry.
Interestingly there is a line of thought that some poorly adapted viruses can be oncogenic (causing cancers)
To everyone with more knowledge on this, please correct and accept my apologies if I butchered anything!
To use your computer analogy, modifying a protein would be like modifying a program class, without fully understanding the full program, might work, might cause huge issues 😂
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It would be quite impossible to do it. Even though mice are used as animal models, they are quite different from us. Here are some differences: First, human cells and mouse cells have a different amount of chromosomes (we have 3 more pairs). Second, we share a lot of genes, but it's quite common that there are some small differences in the sequences of them. So, for example, we both have genes with the same name that will be translated into proteins with similar funcions, but when we compare the molecules in detail they have a few differences. And third, we have a lot of genes that are species specific, so they can only be found in humans. With CRISPR we could add a human gene to a mouse stem cells, but this would be a very punctual and precise change to the DNA of those cells.
And if you really want to get your mind blown you might want to look into epigenetics. So basically, how the DNA is folded down into the cell can determine which genes are "read" and translated into protein. Because of epigenetics a neuron and skin cell, which have the same DNA, can perform entirely different functions.
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dan_dares t1_irmcp1t wrote
CRISPR is a scalpel, able to excise and introduce new DNA, potentially it's possible to change all the DNA in a mouse cell, but it would be like trying to change a painting with a single hair paintbrush.
Given the number of times you'd need to conduct the protocol, you'd need to culture the cell line for quite a while, to be honest I think that would be a limiting factor.
My wife has actually used CRISPR on mouse lines for genetic studies but they have always been for small knock-ins and knock-outs.
EDIT: Sorry, missed a part to expand on..
If we presume that you could wave a wand and change the DNA using CRISPR all at once, you would have a situation where proteins being created would be different from the existing proteins, not sure what the ramifications of this would be, I shall ask my better half.
Gut feel is there is a possibility that the cell might undergo apoptosis during the change over, for a few reasons..