The University of New South Wales (UNSW) in Australia, along with Memphis-based St. Jude Children’s Research Hospital, have discovered and demonstrated a new form of CRISPR. This gene editor has been featured in numerous postings to this site.
A CRISPR Backgrounder
Jennifer Doudna first described CRISPR’s capabilities in an article appearing in the journal Science back in 2012. Later, she wrote the book, A Crack in Creation: Gene Editing and the Unthinkable Power to Control Evolution, describing the power of this genetic rewriter to cure diseases, enhance biology, address world hunger, and alter humanity.
CRISPR/Cas9 was the laboratory tool that Doudna used to snip out bad genes and replace them. This was the 1st generation of the tool. The 2nd generation could zoom into DNA strands and correct individual nucleotides.
What UNSW has done is introduce a 3rd-generation CRISPR editor that turns genes on by removing methylation marks, small chemical tags that signal and control gene expression. Methylation marks play a significant role in how DNA responds to diseases like cancer. Too many methylation marks suppress genes that could help fight a particular disease.
Removal of promoter CpG methylation by epigenome editing reverses HBG silencing, is the name of the paper published July 27, 2025, in Nature Communications, that describes the collaboration between UNSW and St. Jude. The paper describes how this 3rd-generation CRISPR is no longer slicing and dicing DNA, but rather is used to remove unwanted methylation marks with Sickle Cell Disease and β‑thalassemia, two inherited blood disorders.
3rd-Generation CRISPR Tackles Sickle Cell and β‑Thalassemia
Why target Sickle Cell Disease and β‑thalassemia?
Sickle Cell affects hundreds of thousands born with the defect every year. In 2021, there were an estimated 7.7 million living with it. Sickle Cell changes the structure of hemoglobin, the oxygen-carrying molecule found in red blood cells. The deformed, sickle-shaped cells carry less oxygen, leading to anemia and other symptoms. The Lancet reports that Sickle Cell is one of the leading causes of childhood deaths in sub-Saharan Africa and South Asia.
β‑thalassemia is a genetic defect that causes reduced production of β‑globin, one of the two main proteins found in hemoglobin. It causes anemia and other symptoms. Between 80 and 90 million people carry this mutation, with up to 60,000 symptomatic births each year. A 2024 estimate in The Lancet stated that 1.3 million live with the disease and an estimated 11,000 die from it annually.
Targeting Methylation Presents A New Gene Therapy
States Professor Merlin Crossley, Deputy Vice-Chancellor Academic Quality, at UNSW, “Whenever you cut DNA, there’s a risk of cancer. And if you’re doing gene therapy for a lifelong disease, that’s a bad kind of risk. But if we can do gene therapy that doesn’t involve snipping DNA strands, then we avoid these potential pitfalls.”
Removing methylation groups is a new use for CRISPR. Guide RNA directs demethylating enzymes to targeted genomic locations to reactivate suppressed gene expression. Crossley likens this to taking a wrench to bicycle training wheels and removing them to free the big wheels to do their thing.
The Promise of 3rd-Generation CRISPR
Kate Quinlan, a UNSW professor and contributor to the project, sees the potential to use this third-generation CRISPR tool for many other genetic diseases. She notes, “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.”
Crossley notes that the development of this third-generation CRISPR makes it possible to target molecules in individual genes. No doubt, therapeutic CRISPR treatments will emerge to fight diseases that impact crops, trees, and more. Crossley’s words say it all: “This is the very beginning of a new age.”
