
Scientists Unveil the 'Most Clever' CRISPR Gadget So Far - signa11
https://www.statnews.com/2016/04/20/clever-crispr-advance-unveiled/
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entee
The paper takes CRISPR/Cas9 and turns it into a targeting system for an set of
enzymes that allow modification of a single DNA basepair at a specific locus
in the DNA without introducing a double strand break.

The reason this is important is because a double strand break (the result of
standard CRISPR) is a devastating event, introducing a risk of uncontrolled
mutation. However, if you're able to modify a single basepair in the DNA in a
targeted fashion, you eliminate that risk, making it much more practical to
use this technology in the clinic.

There are still absolutely massive obstacles to using CRISPR in a clinical
setting, but this is a very important step forward. It still remains to be
seen how you get the CRISPR/CAS system into a cell (and other ancillary
accessories specified in this work) reliably in a clinical context. Still
early days, but a very important step.

Full disclosure: David Liu (the PI on this work) may be seen as a competitor
to the lab where I did my graduate work.

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patall
So it does prevent failure in NHEJ, doesn't it? But how does it prevent
offtarget effects? I mean, if the wrong guide sequence is bound, an offtarget
is mutated all along, isn't it?

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jessriedel
Does this answer your question, or are you asking something else?

> The problem addressed by the new technique is not the usual one discussed
> with CRISPR, namely, off-target effects. That refers to changing a region of
> the genome other than the intended one. While early genome-editing
> experiments had that problem, there has been “tremendous progress” in fixing
> it, said Dr. Keith Joung of Massachusetts General Hospital.

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patall
Thanks, thats what I was looking for. The first paragraph totally sounded like
they were targetting offtargets, but in the end they dont.

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po
Huh.. this paper introduces a technique that works the way I originally had
understood CRISPR/Cas9 to work based on my casual reading of the technology.
So that's pretty good news and I should apply my previous excitement about it
here I guess!

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gmarx
This is pretty typical of popular press descriptions of new science and tech.
Initially describe it as though it works flawlessly. Reveal flaws only later
in the context of their having been dealt with. I also used to see this a lot
back when I was an audiophile. A new piece of kit would be reviewed as
absolutely amazing and worthy of its huge price. Then a few years later a new
bit of equipment would be praised as improving on the previously reviewed
one's well known flaws.

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daemonk
Cool. So they basically took away Cas9's ability to cut, but retained its
ability to target specific loci on the genome. Then attached an enzyme that
converts the base.

Changing the other combinations of bases might be tricky. Not sure if there
are existing enzymes that will perform those functions biochecmically, as C ->
U conversion is relatively simpler compared to other conversions.

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fourstar
So CRISPR is definitely a hot topic right now, and we hear that it has better
success in vitro rather than in vivo (correct me if I'm wrong), but how far
out is this to being available as a therapeutic mechanism in the treatment of
diseases?

And what diseases are those?

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entee
A major issue is that in vitro you have the luxury of many attempts to get the
right result.

Here's a somewhat simplified but illustrative example:

Say you have 10 mouse embryos. You use CRISPR, then check them for whether it
worked out as expected. Only one of those embryos is as desired.

That's totally fine, and massively accelerates lab research. But you can't
apply those numbers to something like human embryos ethically.

I think (and people I know in academic science agree) that CRISPR is awesome
for research science, but that it's going to take some time before it's
directly useful in the clinic. And even when it is, it's likely to be useful
in a subset of cases where you can check whether CRISPR had the desired effect
before introducing the results into a patient. This is still very useful
(immunotherapy for cancer for example, another very hot topic these days), but
doesn't quite match the breathless statements from the mainstream press.

This work is really nice because it likely reduces the number of embryos (in
the above contrived example) you'd need to screen before finding an
appropriate one. On the other hand it's still very very hard to get this to
work when you have a limited number of cells you can apply CRISPR/CAS to.
Progress, yes. Panacea, no.

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codeulike
And I would have thought that letting an agent that can modify DNA loose
anywhere except strict lab conditions could be dangerous? Do you expect gov
regulations to happen soon in this area?

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tstactplsignore
Not dangerous at all. Requires high concentrations of reagents to function,
can't penetrate cells on it's own, sensitive to pH and solution conditions,
protein doesn't aerosolize on it's own, etc. The government regulates how you
can use it, but cas9 itself is harmless

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tudorw
Why do government and public funds get spent supporting universities to train
specialists to develop then patent important stuff ?

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geyang
There is actually a long history of doing exactly this. In short, the
government (correctly) believes that it is not very good with creating
business, and it is better left in the hands of the private sector.

In terms of the ownership of the intellectual property, the extent to which
these NIH/NSF Grants reach ends with the discovery of the knowledge. These
Grants are not considered benefits or entitlements, but awards to support
specific public purposes. It is a form of transfer payment from the
government. You can consider it a lever for the government to support selected
fields of research, but no more than that. These Grants are designed
specifically to not entitle the funding agency ownership of the discovery.

The government is determined to help the scientists and the institutions to
turn the discoveries into businesses, because only through business can these
insights gained from research benefit consumers. There are specific grants for
this purposes and they have in the past been successful at helping brining
discoveries to market, creating viable small businesses. The idea is that the
ownership of the intellectual property is best bestowed upon those who were
involved in the original discovery. And it is best to leave the creation of
businesses to the private sector, because the government is not very good with
creating businesses directly. If you are looking for an examples of government
being inefficient at running business, you can look at the nuclear power
industry. It is completely government owned because of the obvious homeland
security implications. Yet it continuously operates at a loss.

As a side-note, to address your comment on "universities train these
specialists":

these specialists are not trained by the Universities. These specialists __are
__the universities sans the administrators, There won 't be Harvard without
these PI's. Also, knowledge is useless on paper. It is these specialists who
knows how to use these knowledge who are valuable. Just to give a sense of how
rare(and valuable) these specialists are, in physics and biology (where I have
worked), I noticed that in most of the fields there are usually less than five
lab and their corresponding PI's who are contributing 95% of the most cutting
edge work.

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hackuser
While I generally support private sector solutions, I don't agree that, self-
evidently or absolutely, private business is the only way to do these things.
It's a great tool, but not the solution to all of life's problems.

Also, whether or not private business is the ultimate solution, the
intellectual property still can be free and open. In the IT industry we
probably can name a few examples of free, open IP that facilitated a little
bit of business, such as the Internet, the Web, Email, the IBM PC design, Unix
... maybe a couple of others ...

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JoeCoder_
"changes one-letter misspellings in DNA called point mutations... it could fix
misspellings in DNA that cause Tay-Sachs"

I don't follow. Tay-Sachs is usually (always?) caused by a frameshift, not a
point mutation.

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jcoffland
It's interesting that the mainstream media mostly glossed over the apparent
danger of CRISPR/Cas9 of causing massive mutations. Very exciting stuff but
clearly we have a ways to go yet.

