
CRISPR 2.0 Is Here, and It’s More Precise - nocoder
https://www.technologyreview.com/s/609203/crispr-20-is-here-and-its-way-more-precise/
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drvdevd
The title in Nature: “Programmable base editing of A•T to G•C in genomic DNA
without DNA cleavage”

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.

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88e282102ae2e5b
> they modified the CRISPR associated DNA editing enzyme, cas9

This is incorrect. They modified a separate enzyme that is fused to cas9.

~~~
evincarofautumn
I think that’s what they meant, and said. Cas9 “CRISPR associated protein 9”
is the protein/enzyme that they modified.

~~~
88e282102ae2e5b
I'm definitely getting into hair-splitting territory, but I think it's
important to not conflate modifying a protein with fusing two proteins. It
would be easy to come away from the GP and think that scientists have the
ability to easily change the enzymatic function of Cas9, when in reality
they're effectively just connecting a protein to Cas9 and letting it do its
thing.

~~~
evincarofautumn
Ah, I see what you’re getting at. I agree.

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rflrob
While direct editing of bases will be a really useful tool, I think it's worth
pointing out to any alarmists about human editing that our ability to make
directed changes far outpaces our knowledge of what changes to make (and our
ability to make reasonable guesses about how safe those changes are). Although
there are a relative handful of diseases that have a single, protein coding
change that's responsible (sickle cell, cystic fibrosis, etc), most diseases
are due to multiple variants, many of which are non-coding, interacting with
environmental factors and chance (diabetes, obesity, depression). These kinds
of tools are incredibly useful in the lab for making advances in understanding
disease, but we're a long way off from widespread clinical use, if that is
even in the cards.

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ilyagr
I'm more terrified of bioweapons targeted at people with some specific gene
and attached to a flu virus. Genocide at a push of a button, orders of
magnitude cheaper than a nuclear weapon, no materials other than standard lab
equipment needed. Bond villains, rejoice!

Any reason to hope we won't be able to do this for another hundred years?
Because CRISPR seems awfully close.

~~~
T-A
How would you prevent natural mutations from modifying or disabling the target
mechanism? If you can't guarantee its integrity, the descendants of your air-
born killer virus will be back for you in short order. That, rather than
inability to do it, is what will hopefully prevent it.

~~~
manquer
That's only applicable for relatively rational state actors not insane
extremists who believe such terrible events are required as part of their
faith

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dundercoder
I have two mutations of USH2A, causing blindness. It’s a big gene. This kind
of tech can’t come soon enough.

~~~
freedomben
I too have some bad genes that make life pretty challenging at times. This
type of tech gives me great hope. I wish I were more qualified to work on it
and advance it.

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guelo
I'm sorry to be trying to take away your hope but I just don't see the path
from CRISPR to gene therapy that can cure diseases in adults. CRISPR allows
scientists to modify DNA in individual cells in a lab setting. But it doesn't
help with mass editing DNA in cells throughout the body. I've heard of
experiments where they take white blood cells, edit their DNA, and then
reinject them. But there's currently no way to modify the genes in-place in a
person's retina for example.

~~~
adventured
That's extremely far from the truth. The entire CRISPR field is focused
heavily on being able to mass edit genes in adults in fact.

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.

~~~
nonbel
>"That's extremely far from the truth. The entire CRISPR field is focused
heavily on being able to mass edit genes in adults in fact."

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...](https://www.nature.com/nature/journal/vaap/ncurrent/full/nature24644.html)

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codq
Can CRISPR lead the bald to a full head of hair? A CRISPR hair loss cure would
be worth billions.

~~~
sschueller
I love the answer Gene Roddenberry gave regarding a bald TNG captain.

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."

~~~
wingerlang
I don't really understand it. Is it because they have fixed it to not become
bald in the first place (so no cure needed), or is he just saying no one cares
about it?

~~~
paulintrognon
Because I guess we'll focus our futur minds on more important things than
someone's baldness

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freedomben
One step closer to either utopia or dystopia. I'm not sure which one.

~~~
hasenj
How would this ever cause dystopia?

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Yuioup
Muliticlass society based on who can afford the treatment and those who can't.

~~~
jjjensen90
Don't we already have that in the US and other countries without socialized
medicine?

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adventured
Even countries with socialized medicine have that. If you're rich and
Canadian, you're not going to wait eight months for your procedure, you have
other options that money provides. The same is true in most socialized
medicine nations. There is almost always a superior therapy or doctor
available somewhere in the world if you can afford it.

~~~
dbbk
Eight months is an exaggeration.

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nether
I hope we can cure treatment-resistant depression of genetic origin with this.

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nonbel
In case an author reads this. I tried getting the data from one of the papers:

>"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...](https://www.nature.com/nature/journal/vaap/ncurrent/full/nature24644.html)

It doesn't seem to work (but I haven't used SRA before):

>"The following term was not found in SRA: SRP119577."

[https://www.ncbi.nlm.nih.gov/sra/?term=SRP119577](https://www.ncbi.nlm.nih.gov/sra/?term=SRP119577)

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shafyy
We've written a short explainer on CRISPR (if you're not familiar with the
basics): [https://humbot.io/How-are-designer-babies-
made](https://humbot.io/How-are-designer-babies-made)

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rimher
Hopefully this is going to be great news. I can't believe how fast the
research with CRISPR is moving, and can't wait to see what's next!

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Sniffnoy
What on earth is up with the paywall on this site? It won't let me read the
non-mobile version at all.

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drcross
"It’s Way More Precise", Is this good English in 2017?

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matheweis
How are we claiming to be able to precisely edit DNA when we can’t even
properly sequence it all yet - from just a couple days ago:
[[https://news.ycombinator.com/item?id=15534325](https://news.ycombinator.com/item?id=15534325)]?

