Scientists at UNSW Sydney have developed a new form of CRISPR technology that could make gene therapy safer while also resolving a decades-long debate about how genes are switched off. The research shows that small chemical markers attached to DNA actively silence genes, rather than simply appearing as harmless byproducts in inactive regions of the genome.
For years, researchers have questioned whether methyl groups, tiny chemical clusters that collect on DNA, merely show up where genes are already turned off or whether they are the direct cause of gene suppression.
In a study published recently in Nature Communications, researchers from UNSW, working with colleagues at the St Jude Children's Research Hospital (Memphis), demonstrated that removing these chemical tags causes genes to become active again. When the tags were added back, the genes shut down once more. The results confirm that DNA methylation directly controls gene activity.
"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."
CRISPR, short for Clustered Regularly Interspaced Short Palindromic Repeats, is the foundation of modern gene-editing technology. It allows scientists to locate specific DNA sequences and make targeted changes, often replacing faulty genetic code with healthy versions.
The system is based on a natural defense mechanism found in bacteria, which use CRISPR to recognize and cut up the DNA of invading viruses.
Early versions of CRISPR tools worked by cutting DNA to disable malfunctioning genes. Later versions became more precise, allowing scientists to correct individual letters in the genetic code. However, both approaches rely on breaking DNA strands, which can lead to unintended changes and increase the risk of serious side effects.
The latest version, known as epigenetic editing, takes a different approach. Instead of cutting DNA, it targets chemical markers attached to genes inside the nucleus of each cell. By removing methyl groups from genes that have been silenced, researchers can restore gene activity without altering the underlying DNA sequence.
New Possibilities for Treating Sickle Cell Disease
The team believes this approach could lead to safer treatments for Sickle Cell-related diseases. These inherited conditions affect the shape and function of red blood cells, often causing severe pain, organ damage, and shortened 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," Prof. Crossley says.
"But if we can do gene therapy that doesn't involve snipping DNA strands, then we avoid these potential pitfalls."
Rather than cutting DNA, the new technique uses a modified CRISPR system to deliver enzymes that remove methyl groups. This process releases the genetic brakes that keep certain genes switched off. One key target is the fetal globin gene, which helps deliver oxygen before birth. Reactivating this gene after birth could help bypass defects in the adult globin gene that cause Sickle Cell diseases.
