New CRISPR breakthrough could transform genetic disease treatment

For years, researchers have been trying to figure out how to treat inherited blood disorders like sickle cell disease without causing new health problems in the process. Now, a team of scientists from UNSW Sydney and St. Jude Children’s Research Hospital has taken a major step forward. By using the latest generation of CRISPR tools, they’ve shown that it’s possible to turn dormant genes back on by simply removing chemical “anchors” that hold them in an off position.

Their findings, published in Nature Communications, offer strong evidence that these chemical tags—called methyl groups—don’t just sit idly on DNA as harmless bystanders. Instead, they play an active role in shutting genes down. The breakthrough not only confirms a long-standing debate in genetics but also points to a safer approach for treating diseases caused by faulty blood proteins.

Scientists have known since the late 1970s that genes can be silenced when small chemical clusters called methyl groups attach to DNA. But whether these groups were the cause of gene shutdown or simply markers of it remained an open question.

The new research settles the debate. Using advanced CRISPR-based methods, the team demonstrated that when these tags were removed, silent genes switched back on. Adding them again turned the genes off once more. “We showed very clearly that if you brush the cobwebs off, the gene comes on,” says study lead author Professor Merlin Crossley, Deputy Vice-Chancellor Academic Quality at UNSW. “And when we added the methyl groups back to the genes, they turned off again. So, these compounds aren’t cobwebs—they’re anchors.”

This work highlights just how central DNA methylation is to gene regulation and why rethinking how to control it could unlock new therapies.

CRISPR started as a bacterial defense system, first spotted when microbes were observed cutting apart invading virus DNA. Scientists soon realized they could harness this ability to edit genes in human cells.

The first CRISPR tools worked by cutting DNA to disable faulty genes, a promising but risky strategy. The second wave refined this by correcting specific “letters” in the DNA code. Yet both methods required slicing into the genetic material, which carries a real risk of introducing harmful side effects, including cancer.

The latest generation—known as epigenetic editing—takes a different approach. Instead of cutting DNA, scientists edit the “surface” of the genome. This involves removing or adding chemical tags that act like on/off switches for genes. By lifting these molecular brakes, researchers can restart genes that are normally silent in adult cells.

Sickle cell disease results from a mutation in the adult form of the hemoglobin gene, which makes red blood cells hard and misshapen. These cells can block blood vessels, trigger severe pain, and shorten lives. But humans are born with another form of hemoglobin—the fetal version—that does the same job of carrying oxygen during development in the womb. After birth, this fetal gene is switched off and replaced by the adult version.

The new approach revives that fetal gene, offering a clever workaround for the defective adult one. “You can think of the fetal 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.”

If successful in clinical use, the therapy would begin with collecting a patient’s own blood stem cells. In a lab, researchers would use epigenetic editing to erase the methyl groups from the fetal hemoglobin gene, switching it back on. The edited cells would then be returned to the patient’s body, where they would start producing healthier red blood cells.

The advantage of this method is that it avoids cutting the DNA itself, reducing the danger of introducing new mutations. “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,” Crossley says. “But if we can do gene therapy that doesn’t involve snipping DNA strands, then we avoid these potential pitfalls.”

Co-author Professor Kate Quinlan adds that the potential goes beyond sickle cell. “Our study shows that epigenetic editing allows us to boost gene expression without modifying the DNA sequence,” she explains. “Therapies based on this technology are likely to have a reduced risk of unintended negative effects compared to first- or second-generation CRISPR.”

So far, the experiments have only been carried out on human cells in laboratory conditions. The next steps include testing in animal models before moving on to clinical trials. If those prove successful, this method could be used in hospitals within the next decade.

Beyond sickle cell disease, the findings open the door to treating a wide range of conditions where silenced genes play a role. Crossley says the technology could even extend to agriculture, allowing farmers to switch genes on or off in crops and livestock without changing their DNA sequences. “This is the very beginning of a new age,” he says.

The link between DNA methylation and gene silencing was first noted in 1979, when researchers studying chickens observed that methyl groups attached to gene promoters correlated with the shutdown of gene activity. Later, scientists found that a global demethylating drug called 5-azacytidine could reactivate fetal hemoglobin genes (HBG1 and HBG2) in humans and primates. This confirmed a strong connection between methylation and gene silencing.

Still, the question remained: was methylation the actual cause of silencing, or just a byproduct? Recent work had even cast doubt on the role of methylation in repressing hemoglobin genes. Studies using CRISPR-based genetic screens identified a protein called UHRF1 as a key player in maintaining DNA methylation and silencing these fetal genes. When UHRF1 was removed in adult red blood cell precursors, the fetal hemoglobin genes switched back on, but adding methyl groups back at the gene promoters silenced them again.

Together, these findings laid the groundwork for the new UNSW and St. Jude study, which demonstrated that the connection between methylation and gene repression is not merely correlative but causal.

If this new form of CRISPR therapy proves safe and effective, it could transform how genetic diseases are treated. For patients with sickle cell disease or beta-thalassemia, it would mean fewer complications, less pain, and longer lives without the risks of traditional DNA-cutting therapies.

The approach could also apply to other disorders caused by gene misregulation, from metabolic conditions to certain cancers. And because the technology doesn’t permanently change DNA, treatments may be easier to control, fine-tune, and reverse if needed.

Beyond medicine, the technique could change agriculture and biotechnology. Farmers might be able to adjust gene expression in crops to boost yield or resistance without crossing into the more controversial realm of direct genetic modification.

By confirming the role of methylation as a true gene switch, this research has set the stage for a new generation of treatments that are precise, flexible, and safer.

Note: The article above provided above by The Brighter Side of News.

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