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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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September 5, 2013

CRISPR Takes Off

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Posted by Derek

If you haven't heard of CRISPR, you must not have to mess around with gene expression. And not everyone does, true, but we sure do count on that sort of thing in biomedical research. And this is a very useful new technique to do it:

In 2007, scientists from Danisco, a Copenhagen-based food ingredient company now owned by DuPont, found a way to boost the phage defenses of this workhouse microbe. They exposed the bacterium to a phage and showed that this essentially vaccinated it against that virus (Science, 23 March 2007, p. 1650). The trick has enabled DuPont to create heartier bacterial strains for food production. It also revealed something fundamental: Bacteria have a kind of adaptive immune system, which enables them to fight off repeated attacks by specific phages.

That immune system has suddenly become important for more than food scientists and microbiologists, because of a valuable feature: It takes aim at specific DNA sequences. In January, four research teams reported harnessing the system, called CRISPR for peculiar features in the DNA of bacteria that deploy it, to target the destruction of specific genes in human cells. And in the following 8 months, various groups have used it to delete, add, activate, or suppress targeted genes in human cells, mice, rats, zebrafish, bacteria, fruit flies, yeast, nematodes, and crops, demonstrating broad utility for the technique. Biologists had recently developed several new ways to precisely manipulate genes, but CRISPR's "efficiency and ease of use trumps just about anything," says George Church of Harvard University, whose lab was among the first to show that the technique worked in human cells.

CRISPR stands for Clustered Regularly Interspaced Short Palindromic Repeats, a DNA motif that turns up a lot in bacteria (and, interestingly, is almost universal in the Archaea). There are a number of genes associated with these short repeated spacers, which vary some across different types of bacteria, but all of them seem to be involved in the same sorts of processes. Some of the expressed proteins seem to work by chopping up infecting DNA sequences into chunks of about 30 base pairs, and these get inserted into the bacterial DNA near the start of the CRISPR region. RNAs get read off from them, and some of the other associated proteins are apparently there to process these RNAs into a form where they (and other associated proteins) can help to silence the corresponding DNA and RNA from an infectious agent. There are, as you can tell, still quite a few details to be worked out. Other bacteria may have some further elaborations that we haven't even come across yet. But the system appears to be widely used in nature, and quite robust.

The short palindromic repeats were first noticed back in 1987, but it wasn't until 2005 that it was appreciated that many of the sequences matched those found in bacteriophages. That was clearly no coincidence, and the natural speculation was that these bits were actually intended to be the front end for some sort of bacterial variant of RNA interference. So it has proven, and pretty rapidly, too. The Danisco team reported further results in 2007, although as that Science article points out, they now say that they didn't come close to appreciating the technique's full potential. By 2011 the details of the Cas9-based CRISPR system were becoming clear. Just last year, the key proof-of-principle work was published, showing that an engineered "guide RNA" was enough to target specific DNA sequences with excellent specificity. And in February, the Church group at Harvard published their work on a wide range of genetic targets across several human cell lines, simultaneously with another multicenter team (Harvard, Broad and Mcgovern Institutes, Columbia, Tsinghua, MIT, Columbia, Rockefeller) that reported similar results across a range of mammalian cells.

Work in this field since those far-off days of last February has done nothing but accelerate. Here's an Oxford group (and one from Wisconsin) applying CRISPR all over the Drosophia genome. Here's Church's group doing it to yeast. There are several zebrafish papers that have appeared so far this year, and here's the Whitehead/MIT folks applying it to mouse zygotes, in a technique that they've already refined. Methods for enhancing expression as well as shutting it down are already being reported as well.

So we could be looking at a lot of things here. Modifying cell lines has just gotten easier, which is good news. It looks like genetically altered rodent models could be produced much more quickly and selectively, which would be welcome, and there seems no reason not to apply this to all sorts of other model organisms as well. That takes us from the small stuff (like the fruit flies and yeast) all the way up past mice, and then, well, you have to wonder about gene therapy in humans. Unless I'm very much mistaken, people are already forming companies aiming at just this sort of thing. Outside of direct medical applications, CRISPR also looks like it's working in important plant species, leading to a much faster and cleaner way to genetically modify crops of all kinds. If this continues to work out at the pace it has already, the Nobel people will have the problem of figuring out how to award the eventual prize. Or prizes.

Comments (10) + TrackBacks (0) | Category: Biological News


COMMENTS

1. Toad on September 5, 2013 10:07 AM writes...

Derek,

You need to embed a reference link for the quote.

Permalink to Comment

2. Sebastian on September 5, 2013 10:10 AM writes...

"Like"! This is the sorta thing that made me want to become a scientist to begin with.

Permalink to Comment

3. hmm on September 5, 2013 2:15 PM writes...

CRISPR has higher off-target effect and which would be a critical limitation for its application. TALENs might still be a better way for genome engineering.

Permalink to Comment

4. Mad Dag on September 5, 2013 2:38 PM writes...


WHOA! Who needs steroid injections to boost athletic performance; that was so last century.

I can't wait to see the next generation of CRISPR athletes.

Permalink to Comment

5. Anonymous on September 5, 2013 3:26 PM writes...

@3,
The recent Cell paper from Zhang's group at Broad/MIT addresses this. They've already been able to reduce off-target effects by 50-1500-fold.

Permalink to Comment

6. Pennpenn on September 5, 2013 6:39 PM writes...

I have to wonder if CRISPR was a lucky coincidence on the name, or they actually took time to get an appropriate acronym that sounded like something? Maybe Mad Dag's CRISPR athletes could end up known as "Crispies"...

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7. srp on September 7, 2013 4:26 PM writes...

Speculation: If a Nobel is awarded, the Danisco folks will get stiffed. Applied industry types, you know.

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8. eugene on September 8, 2013 1:26 AM writes...

Sorry about the ignorant question wrt gene therapy in humans that Derek mentioned (I'm just a plain chemist), but how would that work in practice? Do you just inject a person with a whole bunch of bacteria with the appropriately trained CASIII units and hope they all go into the human cells that express that gene badly? So, maybe in some particular organ (that makes too much amyloid protein for example)? And that would only work for diseases in which you need the gene silenced and not where it's expressed incorrectly, right?

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9. prasad on September 8, 2013 9:47 AM writes...

Eugene, I am guessing that it would be by engineering stem cells ex vivo (in a dish) through CRISPRs and pushing them back into the body. That would work for correcting a dysfunctional or poorly functional gene. Not sure about a protein that is functioning well and wreaking havoc.

Permalink to Comment

10. Dakota on January 26, 2014 4:49 PM writes...

Can anyone identify which corporate bio labs are running early phase on this technique? Thnx.

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