Scientists have genetically engineered monkeys so that they exhibit behaviours similar to autism, with a goal of testing potential therapies on the animals in hopes that their resemblance to humans will yield more answers about the disorder.
The scientists found that the monkeys showed "very similar behaviours related to human autism patients, including repetitive behaviours, increased anxiety and most importantly, defects in social interactions," said Zilong Qiu, a leader of the research at the Institute of Neuroscience at the Chinese Academy of Sciences in Shanghai. The team is now imaging the brains of the monkeys, he said, "trying to identify the deficiency in the brain circuits that is responsible for the autism-like behaviour".
The research, published in the journal Nature, appears to be the furthest along of several research efforts involving monkeys, usually marmosets or macaques, engineered with genes linked to autism.
Much autism research has focused on mice because they are inexpensive and reproduce quickly. Although mice engineered with other genes have developed some autism-like behaviours, the complexity and variability of autism are difficult to study in those less-advanced animals.
"Mice are not in the same league when you're talking about doing models of social cognition and interaction," said Jonathan Sebat, chief of the Beyster Centre of Psychiatric Genomics at the University of California San Diego, who was not involved in the monkey research. "They're not even close."
Not only are mouse brains simpler than primate brains, but "mice reach maturity in a matter of months, and that doesn't give you a lot of time to study their development," said Sebat. "It's very logical that a primate would make a better model of human development and neurodegeneration. It's a no-brainer."
Previously, US scientists have created monkeys with the mutation for Huntington's disease.
At the Institute of Neuroscience in China, other researchers are creating monkeys with genes linked to neuromotor and psychiatric disorders, said the director, Mu-Ming Poo.
The overarching cause of autism is still unknown, and cases have been linked to about 100 mutations, some inherited and some developing spontaneously.
The monkeys in the newly published research did not exhibit every aspect of autism or even every aspect of the genetic autism-like disorder the scientists were seeking to mirror. That disorder, MECP2 duplication syndrome, occurs when people, especially boys, inherit two copies of the MECP2 gene.
The scientists used an inactive virus to inject the human MECP2 gene into eggs of female monkeys and then artificially inseminated the eggs and implanted the embryos into surrogate monkeys. They ended up with eight carrying the gene in the cortex and cerebellum of their brains.
The monkeys did not all have two copies of MECP2, as in the human syndrome, but most had more MECP2 than normal, an overexpression of the gene. The genetic change and the social deficits were also transmitted to a second generation of monkeys, Qiu said.
These monkeys were more likely than normal ones to run in circles in their cages, which the scientists considered an example of repetitive behaviour. They showed more stress and defensive behaviour, grunting more when people gazed at them, which the scientists said reflected autism-like anxiety. And they were less likely to be social by sitting with, touching or grooming other monkeys.
As the monkeys got older, males showed more social disconnection, just as MECP2 syndrome is more common in boys, the researchers said.
But the monkeys also had significant limitations as models for MECP2 duplication syndrome and for autism in general, said Dr Huda Zoghbi, professor of neuroscience and molecular and human genetics at Baylor College of Medicine.
Zoghbi, who helped discover that mutated forms of MECP2 cause Rett Syndrome, a type of autism that mostly affects girls, said the monkeys only carried MECP2 in neurons, not throughout the brain, as happens in humans. She questioned whether circling the cages was akin to repetitive behaviour in autism, and noted that the monkeys did not exhibit some crucial features of MECP2 duplication syndrome, like seizures and cognitive deficits.
"The model shows us that you can make transgenic monkeys using this protein and you can get behavioural symptoms," she said. "Is this model like the human disease? That's where the differences arise."
Genetically engineering monkeys is much more costly and time-consuming than making transgenic mice, said Dr Anthony Chan, whose research involves transgenic Huntington's disease monkeys at Yerkes National Primate Research Centre in Atlanta.
Producing enough monkeys to test therapies takes years, he said, adding that an experiment like the Chinese one would cost "a few million dollars", and would be more expensive in the United States because of labour costs and less availability of monkeys, which are indigenous to China.
Also, some animal rights advocates are more troubled by research on monkeys than research on rodents.
Still, some experts said in some circumstances, monkeys could help scientists better understand how autistic brains work and the effects of approaches like deep brain stimulation, gene therapy or medication. And monkeys, with longer life cycles than mice, may offer better opportunities to observe autism developing from infancy.
"I'm cautiously optimistic about the findings," said Dr Sarika Peters, a clinical researcher in autism at Vanderbilt University School of Medicine, who was not involved in the study. "This could be one possible animal model with relevance to at least a subset of individuals with autism."
Sebat at the University of California San Diego said that MECP2 duplication, which, while rare, is a common genetic cause of autism-like symptoms, "was a logical place to start in making a primate model of autism," but that monkeys engineered with some other autism-linked genes would be better candidates for testing drugs.
Given the expense of engineering monkeys, experts said, mice should be made with various genes first, and "then a subset of these genetic models of autism in mouse can be studied much more intensely in primate models," Sebat said. "The monkey is not going to replace the mouse."
The New York Times