Searching for answers surrounding autism

Replicating a gene linked to autism in a monkey model could shed light on its underpinnings.


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For Guoping Feng, one of the hardest aspects of his work is hearing the anguish of the parents of children with autism. As a professor of neuroscience at the Massachusetts Institute of Technology and a prominent researcher of the mechanisms that underpin neurodevelopmental conditions such as autism spectrum disorder (ASD), Feng hears their distress by email, phone, and visits to his office. “They ask what we can do, and I can’t help them right now,” he says.

Feng’s response is a reflection of the current state of research into ASD, on which much work remains to be done. “You can’t give them false hope, but you want to give them some hope… Just, how do I tell them?”

Despite these emotional struggles, the calls for help received by Feng act as a powerful call to action: “It really motivates me, and the people in my lab to try and do something as quickly as possible to help them.”

Feng, along with a large international collaboration of MIT scientists and researchers from China, has made a breakthrough that may open doors to a greater understanding of ASD. By creating genetically modified macaque with one of the same genetic mutations common to people with autism. This newly-developed ‘model’ of autism now offers scientists more opportunities to study the disorder, and to bridge the understanding between its genetic basis and its debilitating symptoms. Armed with this knowledge, researchers will hopefully be able to devise new therapies for ASD.

The study of ASD 

ASD is a neurodevelopmental disorder that manifests in many ways. The condition usually presents at a very early age; however, affected individuals can reach early adulthood before traits become evident. Autism can significantly affect the ability to communicate, or social functioning. Other symptoms include fixative, repetitive behaviour — including that which causes self-harm.

The global research community has discovered a list of almost 1,000 genes that are implicated in ASD, says Yang Zhou, a former researcher in Feng’s lab at MIT, and lead author of their newly-published Nature study. Zhou has extensively studied animal models for autism for around 10 years, and now continues his research at McGill University in Montreal, Canada.

Autism can be caused by multiple genetic factors, or in some cases, a single, monogenic factor. Zhou and Feng’s study focused on a mutation in the SHANK3 gene, which is present in around 1.5 percent of all cases of monogenic autism. Despite this low percentage, SHANK3 actually constitutes one of the largest single-gene causes of ASD.

“SHANK3 is a gene that encodes a key scaffold protein that forms synapses in the brain,” says Zhou. “The synapse is the main building block required for communication between individual brain neurons.” When SHANK3 is disrupted, neuronal connectivity is impaired, leading to brain circuitry changes that could contribute to the array of symptoms seen in autism.

Zhou, Feng, and their team previously studied autism in rat models, in which gene editing tools have long allowed for inducing the condition. But rat models can only offer so much. As Feng explains, every animal’s brain, emotions, and behaviour develop through the process of evolution to best suit the particular needs of that animal. As a result, a rat’s brain is very different than a human brain. A monkey’s is closer. However, until just a few years ago, there was reliable technique to genetically modify a monkey.


The team’s big break came in the form of CRISPR-Cas9, a gene-editing tool discovered and refined over the last 10 years. 

CRISPR gene editing involves the DNA-cutting protein Cas-9 bound to a guide RNA — a short sequence of genetic material that seeks and binds a complementary section of DNA, which Cas-9 then cleaves. Through the selection of specific guide RNAs and the alteration of the Cas-9 complex, scientists can now disable certain genes, increase their expression, or introduce new genes entirely.

In the past, Zhou says, they’d need thousands of embryos to successfully create an edited one. With CRISPR, scientists can now get five edited embryos out of 10. Some teams have reported up to a 90 percent efficiency.

The team created five macaques with damaged SHANK3 genes, producing lower levels of functional SHANK3 protein, and inducing autism-like symptoms. The macaques manifested repetitive behaviour, interaction issues, motor function issues, and an inability to fall into a deep sleep — all hallmarks of ASD in humans. 

But perhaps the biggest breakthrough in the team’s experiments was that the mutations induced in the monkeys were carried through germline transmission, meaning the mutations were hereditary, and could be passed on through reproduction to the next generation of macaques. 

Empowering future science

The model devised by Zhou, Feng, and their team can now be leveraged to gain greater insights into the cause and effects of ASD. For instance, says Zhou, research efforts are now underway to develop artificial intelligence-powered systems to observe ASD model macaques and better understand the details of autism’s impact. Future studies may use this model to study the effects of gene therapies that might revolutionize the treatment of autism. Using MRI and EEG scans, researchers may be able to identify signatures of the disease in brain activity, providing clinicians with a reliable set of biomarkers to more easily and objectively diagnose ASD in children.

With these prospective future discoveries, the parents who contact Feng may be able to see their children benefit from the treatments they seek. Until then, they remain supportive of his work, “many of them help us,” he says. “They fundraise for donations, seeing that science is the way to give hope to their kids.”

“We’re very grateful, and very motivated by them,” he adds.


  1.  Zhou, Y., et al. Atypical behaviour and connectivity in SHANK3-mutant macaques. Nature 570 326–331 (2019) | article

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