Niu et al., Cell

Twin cynomolgus monkeys born in China are the first with mutations in specific target genes.

The ultimate potential of precision gene-editing techniques is beginning to be realised. Today, researchers in China report the first monkeys engineered with targeted mutations1, an achievement that could be a stepping stone to making more realistic research models of human diseases.

Xingxu Huang, a geneticist at the Model Animal Research Center of Nanjing University in China, and his colleagues successfully engineered twin cynomolgus monkeys (Macaca fascicularis) with two targeted mutations using the CRISPR/Cas9 system a technology that has taken the field of genetic engineering by storm in the past year. Researchers have leveraged the technique to disrupt genes in mice and rats2, 3, but until now none had succeeded in primates.

"This is an important step," says Feng Zhang, a synthetic biologist who was not involved in the study, but who has helped to develop CRISPR technology at the Massachusetts Institute of Technology in Cambridge. "It shows that the system is working."

Transgenic mice have long dominated as models for human diseases, in part because scientists have honed a gene-editing method for the animals that uses homologous recombination rare, spontaneous DNA-swapping events to introduce mutations. The strategy works because mice reproduce quickly and in large numbers, but the low rates of homologous recombination make such a method unfeasible in creatures such as monkeys, which reproduce slowly.

"We need some non-human primate models," says Hideyuki Okano, a stem-cell biologist at Keio University in Tokyo. Human neuropsychiatric disorders can be particularly difficult to replicate in the simple nervous systems of mice, he says.

Previous attempts to genetically modify primates have relied on viral methods4, 5, which create mutations efficiently, but at unpredictable locations and in uncontrolled numbers. Prospects for primates brightened with the emergence of the CRISPR/Cas9 gene-editing system, which uses customizable snippets of RNA to guide the DNA-cutting enzyme Cas9 to the desired mutation site.

Huang and his team first tested the technology in a monkey cell line, disrupting each of three genes with 1025% success. Encouraged, the scientists subsequently targeted the three genes simultaneously in more than 180 single-celled monkey embryos. Ten pregnancies resulted from 83 embryos that were implanted, one of which led to the birth of a pair with mutations in two genes: Ppar-, which helps to regulate metabolism, and Rag1, which is involved in healthy immune function.

Stem-cell researcher Rudolf Jaenisch of the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, calls the result an interesting demonstration, but says that it offers little scientific insight. "The next step is to see if we can learn anything from it," says Jaenisch, who pioneered the use of transgenic mice in the 1970s.

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First monkeys with customized mutations born

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