markus matzel/ullstein bild via getty images
A team of Chinese scientists used genetically ** to correct a mutation that caused mice to exhibit autistic behaviors such as ADHD, repetitive self-grooming, and abnormal social interactions. Once the genetic mutation is repaired, the behavior of these animals returns to normal.
An article published in the journal Nature Neuroscience at the end of November described the experiment, which is the first successful attempt to use genome editing technology to reverse autistic behavior in an animal model of autism spectrum disorder (ASD). ASD refers to a variety of disorders characterized by challenging social skills, repetitive behaviors, and poor communication. These behavioural difficulties can range from barely noticeable to severely diminished. In the United States, 1 in 36 children has autism.
Autism is thought to be caused by a combination of environmental and genetic factors. But while scientists have struggled to convincingly hint at specific environmental impacts, they have identified genes that, once mutated, greatly increase the risk of developing autism. One of these genes is called MEF2C. It is directly involved in the growth of skeletal muscle and the formation of blood vessels and may play a role in the structure of the cerebral cortex. Mef2C mutations can cause severe autism in humans. These people usually don't speak, may grind their teeth incessantly, and may also suffer from epilepsy.
ASD and base editing
In their experiments, the researchers genetically engineered a mouse that carried the mutant Mef2C gene. These mice exhibited significant autistic behaviors compared to the unchanged mice. They then used a type of genome editing called base editing to correct the mutation. You see, these rats are starting to behave like their companions.
Genome editing has been synonymous with CRISPR-Cas9 for years. Base editing is a recent advancement, dating back to 2016. CRISPR-Cas9 is essentially a chainsaw that cuts off parts of the DNA strand, while base editing is more like a scalpel targeting individual nucleotides (A, T, C, G) on the DNA strand. CRISPR can make large-scale changes, but sometimes it fails, cleaving unexpected parts of DNA. Although base editing is much more precise, it can only make minor changes to the genome.
In the current experiment, all that is needed is a minor change. Base editing corrected autistic behavior in animals with no significant adverse effects. Another key achievement of this research was to allow editors to cross the blood-brain barrier, a notorious obstacle when it comes to neurological disorders. Scientists have combined their precious payload with an adeno-associated virus** to guide it through the barrier. Often ignored by the immune system, these basic, tiny viruses can integrate into the host's genome without causing harm.
"Taken together, these results establish a framework for using genome editing in the brain to correct genetic mutations and provide a potential approach for patients with inherited neurodevelopmental disorders," the researchers wrote. ”
Proof of concept
Other neurological disorders can also be targeted for base editing, including RTT syndrome, fragile X syndrome, Angelman syndrome, and Pete-Hopkins syndrome.
Overall, I think it's a fascinating observation!Dr. Allison Mutri, a professor of pediatrics, cellular, and molecular medicine at the University of California, San Diego, told Big Think. Some of Muotri's research has focused on the cellular mechanisms behind autism.
He added that the success represents a solid "proof of principle" in the long and tortuous journey of **ASD, and he warned that it will take some time to replicate the method in humans.
"We are still a long way from these experiments, both from safety concerns (these enzymes can have potentially harmful off-target) and from actual delivery (human brains are much larger than mice)," he wrote in an email. "But that's how science works, generating data from relevant model systems and moving in the direction of human application. ”
Another key caveat of current experiments is that base editing only works for small, neat mutations in a single gene. In humans, it is rare to find an example of a mutation that can eventually cause disease in an individual. This means that base editing cannot be used for all forms of autism.
Nor should it be. Most people with autism have even stronger mental abilities than others. As Muotri said in a conversation in 2022, any future genet** may only be used for the individuals most affected by the disease.