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A new generation of CRISPR technology developed at UNSW Sydney offers a safer path to treating genetic diseases like Sickle Cell, while also proving beyond doubt that chemical tags on DNA – often thought to be little more than genetic cobwebs – actively silence genes.

For years, scientists have debated whether methyl groups – small chemical clusters that accumulate on DNA – are simply waste that collects in the genome where genes are turned off.

But now researchers at UNSW and the St Jude Children’s Research Hospital (Memphis), have published a study in Nature Communications that reveals that removing these tags can switch genes back on – confirming that methylation is not just correlated with silencing, but directly responsible for it.

“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.”

What is CRISPR?

CRISPR – otherwise known as clustered regularly interspaced short palindromic repeats – 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.

It uses a naturally occurring process, first observed in bacteria fighting off invading viruses by cutting the virus DNA strands.

The first generation of CRISPR 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.

The third generation – known as epigenetic editing – instead looks at the surface of genes. Rather than cutting DNA strands to remove or edit faulty genes – this method removes methyl groups attached to silenced or suppressed genes.

A potential breakthrough for sickle cell disease

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.

“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,” Professor Crossley says.

“But if we can do gene therapy that doesn’t involve snipping DNA strands, then we avoid these potential pitfalls.”

Instead of cutting, the new method uses a modified CRISPR system to deliver enzymes that remove methyl groups from DNA – effectively lifting the brakes on silenced genes. The foetal globin gene plays a key role in delivering oxygenated blood to a developing foetus in utero, and the researchers say switching it back on following birth could provide a workaround for the faulty gene that causes Sickle Cell diseases.

“You can think of the foetal 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.”

The big picture

So far, all work to achieve this has been carried out in a lab on human cells at UNSW and in Memphis.

Study co-author Professor Kate Quinlan says the discovery is not only promising for people with Sickle Cell disease, but also for other genetic diseases where turning certain genes on or off by altering methyl groups avoids having to cut DNA strands.

“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.

In the future, once testing in animals and clinical trials are complete, doctors could use the method to treat Sickle Cell disease by first collecting some of the patient’s blood stem cells. In a lab, epigenetic editing would be used to remove the methyl chemical tags from the foetal globin gene to reactivate it. The edited cells would then be returned to the patient, where they settle back into the bone marrow and start producing healthier blood cells.

Listen below or download the episode.

 

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Podcast Transcript

​Nancy Volkers: This episode discusses the ILAE’s updated seizure classification published in April 2025 in the journal Epilepsia. The article is available open access on the Epilepsia website, and a figure depicting the updated classification scheme has been translated into 14 languages. Those translations are available within the article in a supplemental PowerPoint file.

Dr. Sandor Beniczky: Hello, my name is Sandor Beniczky. I’m professor at Aarhus University and I’m the head of the clinical neurophysiology department at the Danish Epilepsy Center.

Nancy Volkers: Before we start talking about the updated classification, can you explain a little bit about how you were involved with it?

Dr. Sandor Beniczky: Yes. So together with Professor Eugen Trinka from Salzburg, we chaired the international working group assigned to this task.

Nancy Volkers: Excellent. Thank you so. I think the first question would be why update the seizure classification framework? I believe the most recent classification was published in 2017, so it hasn’t been too many years. What was the thought behind updating it?

Dr. Sandor Beniczky: The 2017 classification was published before it had been broadly tested in clinical practice. So it was expected that adjustments might be needed. The original paper even noted that a few years of real-world use would likely reveal areas for refinement.

While the main structure has proven robust, some challenges have emerged, particularly in epilepsy monitoring units and also in translation to multiple languages, where certain terms were less adaptive.

Nancy Volkers: How does the most recent classification, that is, the one that has just been published in Epilepsia—how does it better serve the epilepsy community?

Dr. Sandor Beniczky: The updated classification is both more streamlined and more flexible. It reduces the number of seizure types from 63 to 21, making it easier to use. At the same time, it introduces descriptors alongside classifiers, allowing for more detailed characterization when needed, such as in the epilepsy monitoring units.

Nancy Volkers: So you mentioned a distinction between classifiers and descriptors. Could you explain a little more what those two terms mean and how the, how they will be used in the classification?

Dr. Sandor Beniczky: Yes, sure. Seizures can be classified along many criteria, and one can end up with a large number of seizure types, but which are the most relevant ones in any classification? You need a guiding principle, a so-called taxonomic rule.

Here the rule is that classifiers have a direct impact on patient management, influencing diagnosis, like syndrome diagnosis, and also treatment decisions. Descriptors, on the other hand, capture important features of the seizures that might guide management when considered alongside other clinical information, but they don’t define the primary seizure type.

Nancy Volkers: Could you give an example maybe of a classifier versus a descriptor?

Dr. Sandor Beniczky: Yes. So an example for a classifier would be impairment or of consciousness or preserved consciousness. An example of a descriptor would be the sequence or long string of seizure semiology within the focal seizure.

Nancy Volkers: Thank you. So there were six key changes listed. And I’d like to just walk through these and you can maybe explain them they were made and what exactly they are. So the first one is, the word “onset” is removed from the names of the four main seizure classes. How does this change classification from a clinical standpoint as well as maybe someone with epilepsy. How does it change their perception?

Dr. Sandor Beniczky: Well, this change in the term just corrected a mismatch between the terminology and its definition. Even in the 2017 classification, generalized seizures were defined as potentially having focal onset with rapid spread through large bilateral epileptogenic networks, and there is compelling evidence from translational and from clinical research that generalized seizures actually have focal onset. And this is not just a technical or scientific detail. It has real clinical significance. Focal features at onset do not necessarily mean that the seizure is focal, which can help avoid misclassification.

Nancy Volkers: Thank you. So the third change is the word “awareness” is replaced by the word “consciousness” as a classifier. And it’s mentioned in the updated classification that “consciousness” is defined by both awareness and responsiveness. So could you explain a little bit the thought behind that replacement?

Dr. Sandor Beniczky: Right. So switching from awareness to consciousness addressed a major criticism of the 2017 classification. Consciousness is a well-established medical term, and as you said, it’s operationally defined as the ability to respond and remember. Awareness alone only captures part of this picture, focusing only on memory. Consciousness covers the broader ability to respond and interact, which is often crucial for clinical assessment.

Information about impaired responsiveness can often be gathered also in the primary care setting. For example the witness reports that he or she tried to interact with the patient during the seizure and received no response or an inappropriate response. This kind of firsthand observation is a critical part of seizure assessment.

Importantly, consciousness is more universally translatable to several languages, which helps with global adoption.

Nancy Volkers: So the fourth key change is that the motor versus non-motor dichotomy is replaced by observable manifestations versus non observable. So can you describe what that means, perhaps with some explanation for non-experts as well?

Dr. Sandor Beniczky: This approach was chosen to better reflect the full range of seizure presentations, particularly for clinical trials, but also in resource-limited areas. It was considered important to emphasize that there are epileptic seizures which do not have any observable clinical manifestation. Just to give you an example, there are other observable manifestations besides the motor phenomena such as autonomic changes. For example, you could observe flushing—that’s observable, yet it’s not a motor phenomenon.

Nancy Volkers: You’re widening the definition a bit by changing it from solely motor versus non-motor to anything that could be observed.

Dr. Sandor Beniczky: Correct. It’s more inclusive.

Nancy Volkers: So the fifth key change is that seizures are described by a chronological sequence of signs and symptoms rather than by relying solely on the first sign. Why was that change made?

Dr. Sandor Beniczky: Yeah, indeed. The entire string of signs, the entire sequence of signs and symptoms is important, especially when we use that to lateralize and localize the seizures, not just the first one. Using the first noted sign for seizure classification was too much in the primary care setting and too little in the specialized centers.

Nancy Volkers: Thank you. And the sixth change is, so you had said that the number of seizure types was reduced from 63 to 21. But there is a new seizure type recognized in the updated classification. And that’s epileptic negative myoclonus. Can you explain why that change was made?

Dr. Sandor Beniczky: Yes. Negative myoclonus has been well documented. And we applied the taxonomic rule and it has implication for syndrome diagnosis, for example, for progressive myoclonic epilepsy. So there was a broad consensus in the working group and also later on during the public hearing on adding this seizure type.

There was a long public hearing process over two months, and we received substantial feedback during the public review phase which was overwhelmingly positive. We made a point of incorporating all constructive criticism we received during the public hearing, especially when it was supported by published evidence.

Nancy Volkers: You also mentioned previously a bit about translating terms into multiple languages. Can you talk about how that was a focus in the updated classification?

Dr. Sandor Beniczky: Well, in this update, we early on included coordinated translations into 14 languages, ensuring that the terminology was clear and consistent globally from the start. The 2017 version was translated after it was published.

Nancy Volkers: So is the hope for this updated classification is that everyone will be sort of speaking the same language ultimately in clinical studies and research and meetings, and you’ll all be using the same terminology and everyone will have the same understanding.

Dr. Sandor Beniczky: Right. Our goal is to promote broad adoption. And without introducing new, unfamiliar terms, I hope we will also achieve that goal. I think by aligning closely with existing medical terminology, this update should be easier to integrate. And of course, we are committed to ongoing education and communication to ensure a smooth transition.

Nancy Volkers: Are there any other points or thoughts that you wanted to share?

Dr. Sandor Beniczky: No, I think we really tackled all the important aspects. The only thing I would like to add is to invite people to read the entire publication. We have detailed explanations and also examples. So in order to understand the internal logic and its clinical usability, it would be important to read the entire paper.

It’s an open access paper. It’s available on Epilepsia, and it’s also listed on the ILAE home page under Guidelines.

Nancy Volkers: Excellent. And I will include links to the paper and there’s an associated commentary in the show notes to this episode.

Dr. Sandor Beniczky: Thank you.

Nancy Volkers: Thank you. Appreciate you coming on the show and telling everyone what they need to know about the updated seizure classification.

RESOURCES

2025 updated seizure classification in Epilepsia

Commentary on the 2025 updated seizure classification

Summary of the updated seizure classification (ILAE website)

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Founded in 1909, the International League Against Epilepsy (ILAE) is a global organization with more than 125 national chapters.

Through promoting research, education and training to improve the diagnosis, treatment and prevention of the disease, ILAE is working toward a world where no person’s life is limited by epilepsy.

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