Monkeys Built to Mimic Autism-Like Behaviors May Help Humans
Scientists have genetically engineered monkeys so that they exhibit behaviors 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 behaviors related to human autism patients, including repetitive behaviors, 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 behavior.”
The research, published Monday 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. Though mice engineered with other genes have developed some autism-like behaviors, 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 Center of Psychiatric Genomics at the University of California San Diego, who was not involved in the monkey research. “They’re not even close.”
“谈到社交认知和互动模式时，小鼠和人类不在一个层次上，”乔纳森·赛巴特(Jonathan Sebat)说。赛巴特是加州大学圣迭戈分校(University of California San Diego)贝斯特精神疾病基因组学研究中心主任，他没有参与猴子的研究。“小鼠和人根本都算不上相近。”
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,” Dr. Sebat said. “It’s very logical that a primate would make a better model of human development and neurodegeneration. It’s a no-brainer.”
Previously, American 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, Dr. 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 behavior. They showed more stress and defensive behavior, 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.
但是作为MECP2重复综合症和更广泛的自闭症的实验模型，猴子仍然存在很大的局限性，贝勒医学院(Baylor College of Medicine)的神经学和分子人类遗传学教授胡达·佐格比博士(Huda Zoghbi)说。
Dr. Zoghbi, who helped discover that mutated forms of MECP2 cause Rett Syndrome, a type of autism that affects mostly girls, said the monkeys carried MECP2 only in neurons, not throughout the brain, as happens in humans. She questioned whether circling the cages was akin to repetitive behavior in autism and noted that the monkeys did not exhibit some crucial features of MECP2 duplication syndrome, like seizures and cognitive deficits.
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 Center 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 labor costs and less availability of monkeys, which are indigenous to China. Also, some animal rights advocates here are more troubled by research on monkeys than by research on rodents.
修改猴子的基因要比修改小鼠的基因成本更高，费时更多，安东尼·陈(Anthony Chan)博士说。他在亚特兰大的叶克斯国家灵长类研究中心(Yerkes National Primate Research Center)以猴子为基因实验体，研究亨廷顿病。他说，等猴子繁殖到足够的数量并试验疗法需要多年时间。他又补充道，像中国这样的试验，一次就要花费“数百万美元”，而在美国，那就更贵了，因为劳动力成本高，猴子的数量少。猴子在中国是土生土长的。另外，美国的动物权利倡导者更厌恶对猴子做实验，而不是啮齿类动物。
Still, some experts said that 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.
Dr. 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,” Dr. Sebat said. “The monkey is not going to replace the mouse.”