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By Dr Kevin Bailey, Technical Analyst at Jumpstart

It is hoped that recent research into genome editing, which allows scientists to change an organism’s DNA at particular locations in the genome, will lead to the development of new ways to prevent and treat human diseases. However, these also raise ethical questions and concerns.

How does it work?

Genome editing works by using certain proteins called nucleases to cut DNA at precise locations and modify gene function. The CRISP/Cas9 system is currently the most versatile and precise method of genetic manipulation and was pioneered by the Jennifer Doudna and Emmanuelle Charpentier laboratories in 2012.

Why is CRISPR the popular option?

CRISPR (clustered regularly interspace short palindromic repeats) enables easy alteration of DNA sequences and modification of gene function. This can be used, amongst other things, to correct genetic defects, treat and prevent diseases or improve crops.

When a phage inserts its genetic material inside the bacterial cell, the bacteria can integrate portions of the genome of the virus within their own genome. CRISPR is adapted from this evolutionary mechanism in bacteria, to defend against attacks by viruses and other foreign bodies.

CRISPR-Cas9 as a genome-editing tool

The protein Cas9 (CRISPR associated protein 9) is an enzyme that, like a pair of scissors, can cut up and destroy the DNA of a foreign invader.

Genome editing involves changing the DNA sequence of an organism. This can be done by inserting a cut in the DNA and tricking a cell’s natural DNA repair mechanisms into introducing the changes one wants.

CRISPR-Cas9 provides a means to do so by localising a specific DNA target, through modification of the RNA sequence and cut both strands of DNA, changing the target and its impact on cell regulation through the introduction of another DNA template.

The CRISPR/Cas9 system has been used to target genes in many cell lines and organism, including humans, bacteria, C.elegans, drosophila, yeast, and monkeys. This versatility is achieved through redesigning of part of the gRNA unit, which changes the specificity of the system. This provides considerable advantages compared to other genome editing tools, enabling rapid genome-wide investigation of gene function through the generation of large gRNA libraries for screening, providing a faster, cheaper and more accurate way of conducting genomic research.

Recent advances and the question of ethics.

Over recent years, much research has been focussed on using the CRISPR/Cas9 system for the treatment of various medical conditions that have a genetic component, including haemophilia, cancer, blindness, cystic fibrosis, AIDS, hepatitis B and high cholesterol.

Research using human cell lines has, to date, been restricted to somatic (non-reproductive) cells, with gene editing in germline (egg or sperm) cells being illegal in the UK and most other countries as there is still much work to be done to improve this system.

Improvements for example on eliminating “off target” effects, where the system cleaves DNA in the wrong place. The increase in knowledge of the DNA sequence of the human genome, and a greater understanding of the behaviours of different Cas9-gRNA complexes can only result in improved specificity. And, in November 2018, the Wellcome Trust Sanger Institute developed a method to predict the exact mutations CRISPR/Cas9 gene editing can introduce to a cell, providing a tool for scientists to research disease mechanism and drug targets using this system.

However, in November 2018, there was one reported incident where this international consensus had been violated by the editing of human embryos using the CRISPR/Cas9 system and subsequent implantation that resulted in a pregnancy and the birth of twins. This raise questions about the ethical consequences of tampering with genomes. Clearly, there is the potential for rogue scientists to use this system in unethical ways and there is a need for a translation research pathway to be developed to enable germline cell editing to be safely applied to human cells.

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