A little trim for your genes

095/366 - Scissors in HDR by Arria Belli on Flickr. Used under Creative Commons license. http://www.flickr.com/photos/arriabelli/2500283558/

(arriabelli/Flickr)

A couple of weeks ago, the news hit that a group of MIT and Harvard researchers were launching a new startup company called Editas Genomics. This in and of itself isn’t particularly novel — new startups launch around Boston nearly every day.

What was different here was their goal: to take a new form of gene editing — of precisely snipping bad or defective gene sequences out of DNA and replacing them with good ones — and turn it into something that could be used for people.

And what’s really cool is how this new method was inspired: by the immune systems of bacteria.

Revision history

Scientists have been able to engineer and edit genes for close to 50 years, since the discovery in bacteria of DNA-chopping enzymes called restriction endonucleases (which can cut DNA at specific points) and the development of technologies to synthesize DNA in the laboratory. Together, these advancements fueled the biotechnology revolution of the 1970s and 80s by giving researchers the tools to make the first transgenic or “genetically-modified” organisms — organisms carrying the genes of other organisms.

And we already can edit genes in people — we call it gene therapy. But it takes more than a couple of enzymes; probably the best technology today (which is still in its experimental stages) relies on a virus to plug the right gene into the genomes of a patient’s cells.

The problem with this technology is controlling where the gene gets inserted. In that, you really can’t. It’s something of a crap shoot: Sometimes the virus will implant itself in a good spot in the genome, sometimes not. For instance, about a decade ago, a gene therapy trial in Europe was halted after several patients developed leukemia. It turned out that the virus used to shuttle the new gene into the patients’ stem cells had inserted itself in such a way as to activate another gene for cell growth, turning the patients’ new cells into cancer cells.†

In addition, viral gene therapy can only be used to add genes. It can’t cut harmful DNA out of a cell.

To really make gene therapy take off, we need a way to really precisely control where the new genes go, and also t take bad genes out. This is where this new gene editing tech comes into play.

Bacterial immunology for fun and profit

A typical bacteria-infecting phage virus. Tevenphage.svg by Adenosine and Pbrosk13 on Wikimedia Commons. Used under Creative Commons license. https://i0.wp.com/upload.wikimedia.org/wikipedia/commons/thumb/5/56/Tevenphage.svg/320px-Tevenphage.svg.png

A typical bacteria-infecting phage virus. (Adenosine & Pbroks 13/Wikimedia Commons)

Just like we get viruses, bacteria get viruses, specifically ones called phages. Phages are little more than tiny packages of genes on stilts. When a phage finds a bacterium it likes, it latches on and injects its genes into the bacterium.

Those genes insert themselves into the bacterium’s genome and take over, using the bacterium’s gene-reading machinery to churn out thousands of baby phages. Depending on the phage, those baby phages then either pop the bacterium or ooze their way out. They then float off to find more bacteria to infect.

But just like we have an immune system, bacteria have an immune system. Their’s based on a genetic feature called the CRISPR system, a set of genes that help them recognize phage DNA and RNA and remember which phages they’ve seen before.

Science writer Carl Zimmer eloquently explained the concept in a post last winter on his blog, but to sum it up, bacteria use CRISPR to ID genetic sequences that come from phages. They then call in proteins called the Cas enzymes to cut up that phage DNA so that the phage can’t make new copies of itself. The system then incorporates some of the phage DNA back into itself so that it can “remember” that phage’s genes and pass that “memory” on to the next generation of bacteria.

The CRISPR/Cas system is very precise when it comes to cutting DNA out of the genome, and unlike the viral gene therapy method I described above, has a kind of cut-and-paste functionality to it. It’s also highly programmable. Want to cut a stretch of DNA, or even a single DNA base, out of a cell and replace it with something else? Load up a CRISPR gene with the sequence you want snipped, inject it into the cell, add a Cas enzyme and the sequence you want to have in there, and wait….the work is done for you. This is why CRISPR has really taken off over the last couple of years as a research tool.

And it’s that programmable specificity that the founders of Editas think will revolutionize gene therapy.

Diagram of the possible mechanism for CRISPR by James atmos on Wikimedia Commons. Used under Creative Commons license. http://commons.wikimedia.org/wiki/File:Crispr.png

A schematic of how CRISPR may work. (James atmos/Wikimedia Commons)

CRISPR isn’t the only player around, mind you. There are two other gene editing technologies in the works, transcription activator-like effector nucleases (or TALENS) and zinc-finger nucleases, which use different enzymes to cut and paste specific DNA sequences. But CRISPR got a big boost last week when two papers came out showing that it could correct gene defects in stem cell-based lab models of disease.

So you could almost say that we’re at the beginning of a gene-editing format war. Who’s going to be the VCR, and who’s going to be Betamax?‡ Only time will tell.

† Disclosure: In my full time job at Boston Children’s Hospital, I’m working with a team that’s running clinical trial using a next-generation viral delivery system developed based on the lessons learned from that European trial.

‡ And with this reference, I have totally dated myself. I’m OK with that. Would this — Who’s going to be BluRay, and who’s going to be HD-DVD? — work better for the younger folks?

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