Scientists Unveil the 'Most Clever' CRISPR Gadget So Far | Hacker News Reader

Scientists Unveil the 'Most Clever' CRISPR Gadget So Far

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88 pointssigna1123 comments

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.

I love when someone digests for me the article and gives just the facts.

HN is particularly great at making the first / best digestion top comment as well

If only HN had tipping like Reddit.

Post your Bitcoin address on your profile page, and the people who care enough will do it

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?

I think the idea is to avoid NHEJ entirely. I would guess that it's going for base-excision-repair (BER), which is why it's currently targeting either C or G bases.

If the wrong guide sequence is bound you're screwed no matter what, though I suspect they'd say that the error rate is low enough to be practically irrelevant. Not sure that's really true though, the genome is pretty big and if you screw up at even astonishingly low rates, you're still screwing up fairly frequently.

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.

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

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!

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.

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.

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?

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.

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?

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

There are so many agents that can modify DNA around you that one more probably doesn't make a difference.

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

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.

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 ...

Because it's has a huge ROI for society. Is there some criticism or implied alternative in your comment that I'm not getting?

"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.

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.

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