Researchers at UNSW Sydney have unveiled a next-generation CRISPR tool that could lead to safer treatments for genetic disorders, including Sickle Cell.
A new generation of CRISPR technology developed at UNSW Sydney offers a safer path to treating genetic diseases like Sickle Cell, while also proving beyond doubt that chemical tags on DNA – often thought to be little more than genetic cobwebs – actively silence genes.
For years, scientists have debated whether methyl groups – small chemical clusters that accumulate on DNA – are simply waste that collects in the genome where genes are turned off.
But now researchers at UNSW and the St Jude Children’s Research Hospital (Memphis), have published a study in Nature Communications that reveals that removing these tags can switch genes back on – confirming that methylation is not just correlated with silencing, but directly responsible for it.
“We showed very clearly that if you brush the cobwebs off, the gene comes on,” says study lead author Professor Merlin Crossley, UNSW Deputy Vice-Chancellor Academic Quality.
“And when we added the methyl groups back to the genes, they turned off again. So, these compounds aren’t cobwebs – they’re anchors.”
What is CRISPR?
CRISPR – otherwise known as clustered regularly interspaced short palindromic repeats – forms the basis of gene-editing technology that allows scientists to find and change faulty sections of DNA – often by replacing them with healthy ones.
It uses a naturally occurring process, first observed in bacteria fighting off invading viruses by cutting the virus DNA strands.
The first generation of CRISPR tools worked in this way, by cutting DNA sequences to disable faulty genes. The second generation allowed researchers to zoom in and correct individual letters in the genetic code. But both approaches involved making cuts to the genetic code, which comes with the risk of unwanted changes that could cause other health problems.
The third generation – known as epigenetic editing – instead looks at the surface of genes. Rather than cutting DNA strands to remove or edit faulty genes – this method removes methyl groups attached to silenced or suppressed genes.
A potential breakthrough for sickle cell disease
The researchers say epigenetic editing could be used to treat people affected by Sickle Cell-related diseases, which are genetic mutations that alter the shape and function of red blood cells – leading to chronic pain, organ damage and reduced life expectancy.
“Whenever you cut DNA, there’s a risk of cancer, and if you’re doing a gene therapy for a lifelong disease, that’s a bad kind of risk,” Professor Crossley says.
“But if we can do gene therapy that doesn’t involve snipping DNA strands, then we avoid these potential pitfalls.”
Instead of cutting, the new method uses a modified CRISPR system to deliver enzymes that remove methyl groups from DNA – effectively lifting the brakes on silenced genes. The foetal globin gene plays a key role in delivering oxygenated blood to a developing foetus in utero, and the researchers say switching it back on following birth could provide a workaround for the faulty gene that causes Sickle Cell diseases.
“You can think of the foetal globin gene as the training wheels on a kid’s bike,” says Crossley. “We believe we can get them working again in people who need new wheels.”
The big picture
So far, all work to achieve this has been carried out in a lab on human cells at UNSW and in Memphis.
Study co-author Professor Kate Quinlan says the discovery is not only promising for people with Sickle Cell disease, but also for other genetic diseases where turning certain genes on or off by altering methyl groups avoids having to cut DNA strands.
“We are excited about the future of epigenetic editing as our study shows that it allows us to boost gene expression without modifying the DNA sequence. Therapies based on this technology are likely to have a reduced risk of unintended negative effects compared to first or second generation CRISPR,” she says.
In the future, once testing in animals and clinical trials are complete, doctors could use the method to treat Sickle Cell disease by first collecting some of the patient’s blood stem cells. In a lab, epigenetic editing would be used to remove the methyl chemical tags from the foetal globin gene to reactivate it. The edited cells would then be returned to the patient, where they settle back into the bone marrow and start producing healthier blood cells.