Chemical Surgery – The Future of Treating Genetic Diseases

Genetic diseases are one of the most challenging problems faced by the medicinal scientific community, how can you cure a problem caused by the faulty instructions encoded by DNA in every cell in your body? For this reason, we still don’t have a means of curing a mature individual with a genetic disease. However with recent scientific advances, we may be able to fix the genetic material of a diseased individual at very early stages in development.

A Chinese research team from Sun Yat-sen University have developed a technique to edit genetic material, which they have utilised to correct the specific mutation resulting in beta thalassemia. Beta thalassemia is a condition caused by what is known as a point mutation. DNA is a long, double-stranded molecule comprised of molecules called nucleotides. Nucleotides each have a distinct base, either adenine (A), guanine (G), cytosine (C) or thymine (T). The order of these bases in the DNA is what codes for the proteins that make up our bodies and enable us to live. In a point mutation, one nucleotide and its associated base is swapped for another, which has the potential to drastically affect the function of the protein the gene codes for if it occurs in a critical place. In many cases of beta thalassemia, an A is swapped for a G. Beta thalassemia is a blood disorder which can lead to anaemia and acute illness, it is potentially life-threatening.

In the most recent decade, one of the most powerful tools for the precise targeting and editing genetic material has been Crispr-Cas9. Crispr-Cas9 is comprised of two main components, Crispr, a length of RNA that guides the molecule towards the relevant area of the DNA. RNA is capable of this due to being a single-stranded nucleic acid, meaning Crispr can be designed to have a base sequence that is complementary to that of relevant gene, causing it to bond to the DNA in the correct place. The Cas9 component is an enzyme that can cleave the DNA. Crispr-Cas9 allows scientists to essentially ‘cut out’ precise sections of DNA, then new sequences can be inserted into the DNA using cellular machinery. While Crispr-Cas9 is undeniably useful, it is not always reliable, as it is possible for it to bind to the wrong place in the genome and then cutting out the wrong section of DNA. Consequently, this technique can often cause more harm than good.

However the team in China have developed a completely new technique that has the potential to offer a level of precision and reliability that surpasses that of Crispr-Cas9 called base editing. Base editing directly corrects the specific base that is causing the mutated form of the protein to be expressed, in this case, changing the faulty G into an A. The technique is remarkably accurate and unlike Crispr-Cas9, does not break up the DNA in the process of correcting it, since the only thing being changed is the faulty base. With Crispr-Cas9, correcting a mutation like this would entail replacing an entire sequence of DNA, so there is far more potential for something to go wrong.

This offers a whole new level of specificity when editing the human genome; however while it may be revolutionary, it is certainly not perfect. The team tested the technique on human embryos with beta thalassemia, and while some were cured as a result of the base editing, others exhibited a mosaic effect. This means that in some individuals, the technique did not succeed within every cell, resulting in them possessing a mixture of cured and mutant cells. This is likely to be a consequence of the paired nature of human chromosomes, resulting in one gene being repaired but not the other.

Clearly there is still work to be done, but the utility of base editing is still undeniable. We are armed with a new weapon to combat genetic disease.

Laura McNamara

References:

1. Gallagher, J. (2017, September 28). DNA surgery on embryos removes disease. Retrieved from http://www.bbc.com/news/health-41386849
2. Whipple, T. & Moody, O. (2017, September 29). DNA surgery removes genetic disease from human embryo. Retrieved from http://www.theaustralian.com.au/news/health-science/dna-surgery-removes-genetic-disease-from-human-embryo/news-story/3db76ed899bce1e7e8acd983db40af7d
3. Sample, I. (2017, September 28). ‘Chemical surgery’ used to mend harmful mutations in human embryos. Retrieved from https://www.theguardian.com/science/2017/sep/28/chemical-surgery-used-to-mend-harmful-mutations-in-human-embryos-base-editing
4. Wilgar, H. (2016, December 19). What is CRISPR-Cas9? Retrieved from https://www.yourgenome.org/facts/what-is-crispr-cas9