CRISPR 2.0 Is Here, and It’s More Precise
technologyreview.com
technologyreview.com
A brief description of what was accomplished (a modification of cas9): “We evolved a tRNA adenosine deaminase to operate on DNA when fused to a catalytically impaired CRISPR-Cas9. Extensive directed evolution and protein engineering resulted in seventh-generation ABEs (e.g., ABE7.10), that convert target A•T to G•C base pairs efficiently (~50% in human cells) with very high product purity (typically ≥ 99.9%) and very low rates of indels (typically ≤ 0.1%).“
Translation: they modified the CRISPR associated DNA editing enzyme, cas9, to “deaminate” (remove or otherwise alter the amino groups) in A-T or G-C pairs without breaking the DNA, as cas9 normally would.
This makes single point precision edits possible, but I’m not sure what that implies for the “guide RNA” cas9 needs to know where to make the edits, as I haven’t read the paper in full yet.
This is incorrect. They modified a separate enzyme that is fused to cas9.
It's also worth considering that conventional western standards of ethics and acceptable risk won't necessarily be a constraining factor on the development of genetic engineering over the next few decades.
"our ability to make directed changes far outpaces our knowledge of what changes to make"
On this point I couldn't disagree more. It's the opposite: our knowledge of what changes to make is years ahead of being able to make those changes. The polygenic scores available for complex traits now, though crude, are within an order of magnitude of what correlations will ever be possible.
For example, the best PGS for educational achievement explains somewhere around ~10% of variance, which corresponds to a correlation of ~32%, and the total heritability is only something like ~75%, meaning the best possible correlation would be ~87%. Anything you can do with a 87% correlation, you can also do with a 32% correlation, and get a proportionately weaker effect.
Of course, there are still many unanswered questions about which SNPs are really causal, and the tradeoffs associated with editing them, but you don't really _need_ this to make edits that are much more likely to help than hurt. As long as you stay within the bounds of what could have happened naturally by chance, the risk really isn't big.
The real problem is that you have to make a _lot_ of edits, and the editing technologies aren't ready for that. I don't know an exact number, but you might be looking at 100s of edits in a single embryo to do anything noticeable. Traditional double-stranded-break CRISPR can't even do 1 edit without usually causing some major damage. Base editing looks better, but still can only do a small proportion of all possible edits.
In conclusion, if you could print an arbitrary human genome, you'd see some pretty sci-fi stuff even today. But we're pretty far off that.
But won't ability to make changes lead to better knowledge of wehat these changes do? E.g. it would make it easier to perform experiments (on non-human species, one would hope) where changes are made and the results studied.
https://en.m.wikipedia.org/wiki/Gene_drive
The potential for good is enormous when it comes to Gene editing. But it's not risk free. (Just like nuclear energy.)
Any reason to hope we won't be able to do this for another hundred years? Because CRISPR seems awfully close.
* In order to get CRISPR to fit inside a virus you have to remove all the viral DNA, so it can't reproduce.
* Even if you could make such a virus, there would be enormous selective pressure to ditch the CRISPR proteins, and there's no pressure maintaining the CRISPR or guide RNA sequence, so it would be inactive pretty quickly
* Race isn't well-defined genetically so it might not even be possible to target a group of interest
* Bombs are cheap and a proven technologyhttps://en.wikipedia.org/wiki/Gene_therapy_of_the_human_reti... is a good place to start.
https://www.quora.com/How-does-the-CRISPR-Cas9-therapy-manag...
The three major CRISPR companies, Berkeley and Broad are all focused on pushing the technology there. It's not a question of if, it's inevitable. They already know it can be done, the challenge is scaling it up and constantly improving the accuracy and the overall command they have of what eg Cpf1 can do (in the case of Broad & Editas).
A very large percentage of all disease occurs in adults after the age of ~30. That is, well after the person is an adult. Take a look at the disease targets that Editas, Intellia and Crispr Therapeutics are pursuing: they're going after adult diseases long-term, including targeting things such as diseases of the liver more near-term (next five years). Most of their initial targets are focused on easier (relative term) editing targets, the retina being a popular target due to the genes there. First they'll learn to crawl, then walk, then run.
You don't have to edit all the genes in the body to cure most genetic diseases.
It doesn't seem so to me. I've noticed less and less focus on toxicity lately, as if they've given up on that. For example, I took a look at one of the papers[1] from TFA. All they look at is percent of sequences from surviving cells that contained the A->G mutation. They don't report how many cells died during the process to get there.
Also, they see these mutations in the control group too (figure 4 untreated A5 = 99.8), so it seems this may be yet another way to use crispr to select for pre-existing mutants. It's hard to say since no info is provided on the toxicity for this new strategy.
On the other hand, the new strategy may be less toxic since it is only supposed to introduce a single strand break rather than double (ie as opposed to cas9). Reviewers should be on this, not sure why they so consistently drop the ball regarding the role of toxicity in these studies.
[1] https://www.nature.com/nature/journal/vaap/ncurrent/full/nat...
I think my hope is really more into something like the Ray Kurzweil cellular-sized nano computers that can be injected into the body to perform various functions. As we understand what causes certain "bugs" in bodies, perhaps an effective solution can be developed.
To deal with complex, higher order genetic diseases (which is also where the money will be in the field) you'll have to be able to do inserting of healthy replacement genes. Cas9 is not very good at that as of now, it's like using a mallet to tie a fishing line. There is an immense amount of effort going into trying to shoehorn Cas9 into being better at that. Other options such as Cpf1 (and possibly one day CasX/CasY from Berkeley) have been shown to be far superior at more advanced editing.
At a press conference about Star Trek: The Next Generation, a reporter asked Star Trek creator Gene Roddenberry about casting Patrick Stewart, commenting that "Surely by the 24th century, they would have found a cure for male pattern baldness." Gene Roddenberry had the perfect response.
"No, by the 24th century, no one will care."
http://ajitvadakayil.blogspot.in/2015/09/ethics-of-human-clo...
If you start a trend, people will follow it. If you give people the ability to modify their DNA people will start copying each other, reducing gene pool diversity. What may seem like a trendy gene modification could quickly turn out to be disadvantageous, or even deadly. Imagine if everyone found it cool to possess the skinny gene. Skinny genes are currently very popular, especially among hipsters, but what if a worldwide famine comes? Of course it can become crazier than that, as there are trends with injecting cement into posteriors, plastic surgery on faces, injecting toxins into faces, huffing glue...
>"High-throughput sequencing data have been deposited in the NCBI Sequence Read Archive database under accession code SRP119577"
https://www.nature.com/nature/journal/vaap/ncurrent/full/nat...
It doesn't seem to work (but I haven't used SRA before):
>"The following term was not found in SRA: SRP119577."