A new generation of CRISPR technology developed at UNSW Sydney offers a safer path to treating genetic diseases like Sickle Cell, while also proving that chemical tags on DNA \u2013 often thought to be little more than genetic cobwebs \u2013 actively silence genes.<\/p>\n
For decades, scientists have debated whether methyl groups \u2013 small chemical clusters that accumulate on DNA \u2013 are simply detritus that accumulates in the genome where genes are turned off, or the actual cause of gene repression.<\/p>\n
But now researchers at UNSW, working with colleagues in the US at the\u00a0St Jude Children\u2019s Research Hospital<\/a>\u00a0(Memphis), have shown in a paper published recently in\u00a0Nature Communications<\/a>\u00a0that removing these tags can switch genes back on, confirming that methylation is not just correlated with silencing, but directly responsible for it.<\/p>\n \u201cWe showed very clearly that if you brush the cobwebs off, the gene comes on,\u201d says study lead author\u00a0Professor Merlin Crossley, UNSW Deputy Vice-Chancellor Academic Quality<\/a>.<\/p>\n \u201cAnd when we added the methyl groups back to the genes, they turned off again. So, these compounds aren\u2019t cobwebs \u2013 they\u2019re anchors.\u201d<\/p>\n A brief history of CRISPR<\/p>\n CRISPR<\/a>\u00a0\u2013 otherwise known as Clustered Regularly Interspaced Short Palindromic Repeats \u2013 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.<\/p>\n It harnesses what is already a naturally occurring process, first observed in bacteria fighting off invading viruses by \u2018snipping\u2019 the virus DNA strands.<\/p>\n The first generation of CRISPR lab 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.<\/p>\n But the third generation \u2013 known as epigenetic editing \u2013 looks at the surface of the genes found in the nucleus of every cell in the body. Rather than cutting DNA strands to remove or edit faulty genes, this method removes methyl groups attached to silenced or suppressed genes.<\/p>\n Sickle Cell diseases<\/p>\n 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.<\/p>\n \u201cWhenever you cut DNA, there\u2019s a risk of cancer. And if you\u2019re doing a gene therapy for a lifelong disease, that\u2019s a bad kind of risk,\u201d Prof. Crossley says.<\/p>\n \u201cBut if we can do gene therapy that doesn\u2019t involve snipping DNA strands, then we avoid these potential pitfalls.\u201d<\/p>\n Instead of cutting, the new method uses a modified CRISPR system to deliver enzymes that remove methyl groups from DNA \u2014 effectively lifting the brakes on silenced genes. The fetal globin gene plays a crucial role in delivering oxygenated blood to a developing fetus in utero, and the researchers say switching it back on following birth could provide a neat workaround for the faulty adult globin gene that has caused Sickle Cell diseases.<\/p>\n \u201cYou can think of the fetal globin gene as the training wheels on a kid\u2019s bike,\u201d says Prof. Crossley. \u201cWe believe we can get them working again in people who need new wheels.\u201d<\/p>\n The big picture<\/p>\n So far, all work to achieve this has been carried out in a lab on human cells in a test-tube at UNSW and in Memphis.<\/p>\n Study co-author\u00a0Professor Kate Quinlan<\/a>\u00a0says the discovery is not only promising for people with Sickle Cell disease, but other genetic diseases where turning certain genes on or off by altering the methyl groups avoids having to cut DNA strands.<\/p>\n \u201cWe 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,\u201d she says.<\/p>\n In a few years \u2013 once testing in animals and clinical trials were complete \u2013 doctors using the new method to treat Sickle Cell diseases would start by collecting some of the patient\u2019s blood stem cells that make new red blood cells. In a lab, they would use epigenetic editing to remove the methyl chemical tags from the fetal globin gene to reactivate it. Then, the edited cells would be returned to the patient, where they settle back into the bone marrow and start producing better-functioning blood cells.<\/p>\n The road ahead<\/p>\n Next the researchers from UNSW & St Jude will test the efficacy of these approaches in animal models but also try more CRISPR related tools.<\/p>\n \u201cPerhaps the most important thing is that it is now possible to target molecules to individual genes,\u201d Prof. Crossley says.<\/p>\n \u201cHere 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.\u201d<\/p>\n Reference: Bell HW, Feng R, Shah M, et al. Removal of promoter CpG methylation by epigenome editing reverses HBG silencing. Nat Commun. 2025;16(1):6919. doi: 10.1038\/s41467-025-62177-z<\/a><\/p>\n This article has been republished from the following materials<\/a>. Note: material may have been edited for length and content. For further information, please contact the cited source. 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