Targeting DNA mutations in disease

Professor John Whitelock explains how new gene targeting and editing technology is helping him investigate and, he thinks, potentially eradicate mutations in the gene that might cause idiopathic scoliosis (bent spine).

Genetic engineering has been undergoing a renaissance in recent years due to the advent of a new way to target and alter genes in a specific manner that is based on an editing system discovered in bacteria. This is known as CRISPR-Cas9 technology and according to Professor John Whitelock, has major biomedical and clinical implications into the future. 

CRISPR (pronounced ‘crisper’) is an acronym for the rather awkward sounding “clustered regularly interspaced short palindromic repeats”, which are segments of DNA containing short, repetitive base sequences. These sequences were first discovered in bacteria as nature’s way of preventing viral infection (i.e. the virus invades the bacteria, the bacterial system recognises these specific CRISPR sequences and is able to cleave and disarm the genetic code of the invading virus, as well as incorporate it into their own genomes to recognise the enemy in the future). Scientists quickly realised this discovery might be useful to human systems because we have similar palindromic sequences in our DNA.

“There are basically two components to how CRISPR-Cas9 works,” explains Whitelock. “There is Cas9 which is an enzyme and acts as a ‘scalpel’ to cut the DNA, and there is a guide RNA (ribonucleic acid) which leads the scalpel to the particular nucleotides in the DNA that it has been sent to cut. The guide RNA is incredibly precise and can find any location in a genome made of billions of nucleotides but, what is really interesting, when it reaches its destination it can trim out a ‘faulty’ DNA sequence and insert a more desirable synthetic replacement part.”

The technology is very new, so it’s early days, but Whitelock, who is a Professor in UNSW’s Graduate School of Biomedical Engineering, says the clinical possibilities are very exciting. “Because CRISPR-Cas9 can be used in the genes of stem cells to investigate which genes are important in the development of different types of tissues and organs, it can also be used in stem cells to target and eliminate a genetic disorder from a gene line, forever,” he continues.

Basically, they’ve cut the mutation out and put new DNA in to rectify and fix it up. That’s pretty impressive work.

Professor John Whitelock, Director, Graduate School of Biomedical Engineering

“I’m currently on sabbatical at the University of Nottingham in the UK, funded by the Leverhulme Trust, on a Visiting Professorial Fellowship with the specific aim to learn how to use the technology to relate to my own research. I’m interested in the gene that has a major role in the development of tissues and organs in embryos and due to its role in building the skeleton, mutations are now known to cause idiopathic scoliosis (or bent spine).”

According to Whitelock, research using CRISPR-Cas9 at the Centre for Biomedical Sciences at the University of Nottingham is already quite advanced and they have successfully used it to fix a genetic mutation in a patient’s DNA that causes sudden cardiac death syndrome. Not in the person yet, but in a culturedish in their laboratory. Whitelock is working with James Smith, an early career post-doctoral scientist and who says that, “recent advances in gene targeting technology mean we are now able to manipulate DNA with more precision than ever before.”

The lab at the University of Nottingham has taken the DNA from a family who have the syndrome; found the mutation in their heart muscle protein; used CRISPR-Cas9 technology to create cell models in stem cells; turned those stem cells into heart cells; shown that the heart cells they’ve made have this mutation; and then, used the same technology to go back in and correct it. “So, basically, they’ve cut the mutation out and put new DNA in to rectify and fix it up. That’s pretty impressive work,” Whitelock says.

“I’m excited to be bringing this technology back to UNSW where we can use it to advance our research into the genes involved in the differentiation of stem cells in some of the common tissue types such as brain and nerve tissue, blood vessel tissue and, bone and cartilage.”

With the unprecedented ability to tweak the DNA of any living creature suddenly unleashed into the world (potential applications include not only eradicating diseases, but stopping mosquitoes spreading malaria, making animal organs suitable for human transplants and even creating designer babies), Whitelock says there needs to be robust debate on the topic and firm regulations put in place to prevent the mis-use of the technology.

“I think the big question, particularly in the ethical world, is ‘Is this playing God?’ and I think that’s a good question that needs to be addressed because gene editing is about changing the fundamental way people are and their genetic make-up passed on through the ages. There are also questions raised about the specificity of the technology with some data suggesting that whilst you’re trying to cut gene A, you might introduce unwanted changes into other genes, but there is time to work through these this and to make sure the system is more robust before we progress it to humans. l think we’re at least 10 years away from seeing it in the clinic,” he says.

Professor John Whitelock and UNSW would like to acknowledge the Leverhulme Trust for supporting his Visiting Professorial Fellowship at the University of Nottingham.

Are you interested in a Scientia PhD Scholarship?

If you are interested in learning more about the research or joining the team in Sydney to complete your PhD with a UNSW Scientia Scholarship, please contact John Whitelock: j.whitelock@unsw.edu.au  

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