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Genome editing with engineered nucleases

As we begin a new year and celebrate the opportunity to pursue the scientific question that excites us the most, I want to visit some of the big stories of the year past, specifically genome-editing using engineered nucleases, the Method of the Year for 2011 according to the journal Nature Methods.

In order to understand the biological function of a protein or a gene, we need to disrupt its expression and observe the changes to the phenotype. However, this is easier said than done. Popularly used methods to achieve this include over-expression, knockdowns or knockouts. These methods do not always work with great precision and sometimes, interpreting the results can be quite challenging. The use of engineered nucleases provides a very precise way of editing the genome and overcoming the challenges posed by the existing methods.

What is the principle behind engineered nucleases that makes them so exciting? Nucleases are enzymes that can cleave the phophodiester bonds between nucleotides in DNA. In response to a double-strand break caused by nucleases, the cell mounts a homologous recombination response to repair the break. Researchers have been harnessing the power of homologous recombination to disrupt genes and induce mutations for a long time now.  But, how do we know where to cause a break to induce the mutation of choice and then, how do we control it? The explosion in gene sequencing provides us the knowledge base for the location of the gene of interest. And now nucleases are being engineered and designed to target a specific sequence or portion of the genome, rather than cause random double strand breaks. It is the precision and specificity of these nucleases that makes them more powerful than previous approaches for genome editing.

The journal Nature Methods highlights not just the method, but also tracks the history behind the development of the method and includes a primer on how genome editing with engineered nucleases work. The precision of genome editing using engineered nucleases can be applied to answer biological questions with even greater detail. There is also considerable excitement in the community about the potential for using this method to target disease causing mutations.

As always, with new methods and discoveries, there are challenges. The method and reagents can be expensive and in the current funding environment, not all labs may have access to them. The hope is that the promise held out by engineered nucleases can overcome the challenges. With that, I wish you a very happy and productive 2012.

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