This CRISPR breakthrough turns genes on without cutting DNA

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."

How CRISPR Technology Has Evolved

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.

"You can think of the fetal globin gene as the training wheels on a kid's bike," says Prof. Crossley. "We believe we can get them working again in people who need new wheels."

What the Research Shows So Far

So far, all experiments have been carried out in laboratory settings using human cells at UNSW and in Memphis.

Study co-author Professor Kate Quinlan says the findings could have far-reaching implications beyond Sickle Cell disease. Many genetic conditions involve genes that are improperly turned on or off, and adjusting methyl groups may provide a way to correct those problems without damaging DNA.

"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.

Looking ahead, the researchers describe how the therapy might one day work in practice. Doctors would collect a patient's blood stem cells, which produce red blood cells. In the lab, epigenetic editing would be used to remove methyl tags from the fetal globin gene, reactivating it. The edited cells would then be returned to the patient, where they could settle into the bone marrow and begin producing healthier blood cells.

The Next Steps in Epigenetic Editing

The research teams at UNSW and St Jude plan to test the approach in animal models and continue exploring additional CRISPR-based tools.

"Perhaps the most important thing is that it is now possible to target molecules to individual genes," Prof. Crossley says.

"Here we removed or added methyl groups but that is just the beginning, there are other changes that one could make that would increase our abilities to alter gene output for therapeutic and agricultural purposes. This is the very beginning of a new age."