Monday, September 14, 2015

A Tale of two CRISPRs

Last year, I had my first "glamour journal" publication, as second author of a Nature Methods paper on a new family of CRISPR-based synthetic regulatory devices.  Actually, I had two "glamour" publications---the other was a Nature Biotech paper on the SBOL language for communicating biological designs with 32 authors, the biggest collaborative publication I've been involved in to date.  That's a tale for another post, however---this one's all about CRISPR, CRISPR, CRISPR.

For those who haven't encountered the wonderful hype-storm around CRISPR, the acronym expands to the highly non-mellifluous "clustered regularly interspaced palindromic repeats," which tells you virtually nothing about why it's cool.  The reason it's cool is because one of the things this awkward acronym refers to a protein ("Cas9") that docks with fairly arbitrary "guide RNA" fragments in order to go act on DNA that matches those sequences.

Core CRISPR mechanism: Cas9 protein binds to gRNA, which targets the protein to a matching DNA sequence

Protein design is really hard, but DNA and RNA design has become reasonably straightforward, so CRISPR is an awesome mechanism: it lets us target a (fairly) predictable protein effect to pretty much any piece of DNA that we want.  People have used it for editing DNA, which has previously been done with lots of other mechanisms, but gets much easier with CRISPR (hence the recent controversies you may have seen in the news around human genetic engineering---the changes we can do aren't any different, they're just a lot cheaper, which is a meaningful difference of a different sort).

Our paper last year showed for the first time how to use the CRISPR mechanisms to make potentially large numbers of strong biological logic gates.  This is important because one of the big things that's been holding synthetic biology back is the difficulty in building reliable computation and control systems inside of cells.  We've known for a long time that biological computing is possible, but there's only been a handful of decent computational devices, and no good ways of making more.  Now, within the last few years, there have been several different families that have emerged, including TALE proteins, homolog mining, invertases, and now, with our paper, CRISPR repressors.  Our CRISPR repressors are nice because they can potentially easily generate thousands of high-performance devices and implement all sorts of complex computations, something that nobody currently has a clear approach for with any of the other families.

Diagram of one of our CRISPR repressors: a modified Cas9 protein (blue box) acts as "power supply" for an inverter logic gate implemented by having the gRNA (orange box) regulate a synthetic promoter (blue arrow). The important things to know are 1) the orange box and blue arrow are easy to design and we can make lots of them that don't interfere with one another, and 2) the blue box can potentially power lots of these gates at the same time.

So I was (and still am) very excited about this publication for two reasons: first because I think it's a big step forward scientifically, and second because it's in a big-name venue that lots of people are likely to pay attention to and where it's more likely to have a big impact on scientific practice.

Just last week, I had my second paper in Nature Methods, led by my same awesome collaborator, Samira Kiani, and following on the subject: this time, our paper shows how to use CRISPR devices to both compute and edit genes in the same circuit.  My reaction, however, has been much more mixed to this publication.  Don't get me wrong: I'm really happy to be published in a high-ranked journal again, and I really enjoy working with Samira (soon to upgrade from Dr. Kiani to Professor Kiani!), who I find an insightful and diligent collaborator and whose skills I think complement my own quite nicely.  Maybe it's just that I can't be so deliriously excited about getting published in a journal a second time?  I'm also not as excited about these results: it's a nice twist on previous results and a useful new capability, but in return we lose some of the device efficacy. Overall, though, I just don't feel like this paper is a game-changer in the way that our first paper might prove to be.

Still, it matters, and it's a step forward for all of us.  Soon, we will meet, celebrate this success with a toast and a fine dinner, and plan our next venture toward transformation of the world and toward posterity.
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