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Science, Maths & Technology

Targeted genome editing: Introducing the CRISPR/Cas9 system

Updated Monday 27th February 2017

Ever heard of CRISPR/Cas9? OU research student, Sonia Azeggagh, explains the impact of this genome editing technology on biology and medicine:

CRISPR/Cas9 is a genome editing technology that has revolutionised biology. Developed in 2012 in a collaboration between the laboratories of Emmanuelle Charpentier and Jennifer Doudna, CRISPR/Cas9 has allowed what were previously powerful yet time-consuming, inefficient and expensive procedures, to become feasible for all laboratories. Highlighting the impact CRISPR/Cas9  has had, the renowned scientific journal Science elected it “Breakthrough of the Year” in 2015.  

Genome editing: modifying DNA by cutting it

All living things contain DNA molecules, which carry the information required for life. Collectively, this information is referred to as the organism’s genome. The individual units of information within each DNA molecule are known as genes. DNA molecules are formed as chains of smaller molecules called nucleotides. The order in which these smaller molecules are arranged – the DNA sequence – determines the information stored in the organism’s genome.

The importance of DNA is such that if a DNA molecule is damaged it must be repaired quickly. To do so, life has developed DNA repair mechanisms. However, DNA repair is not fool proof and small mistakes can be made. Scientists have learned that they can benefit from these error-prone mechanisms to make small targeted changes to the DNA sequence of the organism or cell they are studying.  If the DNA sequence is changed, the information contained in a gene will also be changed. This process, known as “genome editing”, enables scientists to study the function of individual genes and is useful in many applications, including investigating how genetic diseases are caused. Genome editing can be fine-tuned to target any desired DNA sequence, and all manner of gene modifications are possible. Researchers can, in theory, cut, insert, modify or replace any section of an organism’s genome at will.

The technology underlying genome editing involves intentionally damaging a cell or organism’s DNA. To do so, molecules called endonucleases that bind to DNA and act as “molecular scissors”, are used to cut the DNA chain in two. Endonucleases are engineered to only recognise and bind a specific DNA sequence within the gene studied by scientists. The two genome editing techniques that preceded CRISPR/Cas9, known as zinc-fingers nucleases (ZFN) and transcription activator-like effectors (TALENs), both fit this description: endonucleases engineered to bind and cut DNA only within the gene of interest.

CRISPr/Cas9 makes it easy                                                                                                                   

Although ZFNs and TALENs allowed some important advances to be made, engineering an endonuclease to only bind a specific DNA sequences is complicated, time-consuming, and can be very expensive. This was before the development of CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats-CRISPR associated gene 9). CRISPR/Cas9 was originally discovered as an immune system in bacteria, but scientists have simplified and repurposed the system as a revolutionary genome editing technology.

Like the previous methods, CRISPR/Cas9 involves an endonuclease (in this case called Cas9) that cuts DNA molecules at a selected site. It differs in that the endonuclease does not bind the DNA itself. Instead, Cas9 binds to a second molecule called RNA that acts as a “guide”. The guide RNA can be considered the jam in a Cas9-DNA sandwich. RNA is a similar type of molecule to DNA and also has a sequence. It is this guide RNA that binds the DNA. RNA will bind DNA very efficiently only if the RNA sequence and the DNA sequence are matching. If not, they will not bind or will bind very poorly. This means the guide RNA can be designed to bind a specific DNA sequence. RNA binds DNA more accurately than the endonuclease binds DNA, which makes the CRISPR/Cas9 technique as effective as the previous methods, if not better.

However, what makes CRISPR/Cas9 a powerful alternative to previous genome editing technologies lies in its core concept. The key detail is that the endonuclease does not need to be re-engineered every time. Instead it is the guide RNA molecule that needs to be custom-made. This though, is a far easier proposition: guide RNAs can be synthesised in a matter of hours and purchased for as little as £10. CRISPR/Cas9 reduces weeks of work into a matter of days. It is this combination of cost, time and efficiency that have made CRISPR/Cas9 a revolutionary technology. CRISPR/Cas9 is now being introduced as a standard technique in laboratories around the world and its future impact on biology and medicine is beyond estimation.

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