Researchers achieved precise gene modification in monkeys. Image credit: Cell, Niu et al.
It’s a no-brainer that monkeys can serve as good models for human diseases. After all, we are evolutionarily related. But creating monkeys that closely mimic human illnesses is technically challenging because their genomes are as complicated as ours. In a paper just out in the journal Cell, researchers report that they have overcome that technical challenge. They used an increasingly popular gene-targeting method called CRISPR. The method allows them to precisely zoom in on a region of the monkey genome, alter it and create a genetically modified monkey with the properties that researchers want. These monkeys are the first primates produced by the CRISPR system.
Genetically modified monkeys have been made before by using other approaches that are based on, for example, mutated viruses that introduce genes into the primate genome. But these methods are random, inserting foreign genes into the monkey’s genome in a hit-or-miss fashion. The gene-modification approach used by the Chinese team led by Xingxu Huang at Nanjing University, Weizhi Ji at the Yunnan Key Laboratory of Primate Biomedical Research and Jiahao Sha at Nanjing Medical University, precisely deletes specific genes found within the monkey genome.
CRISPR, an acronym that stands for Clustered Regularly Interspaced Short Palindromic Repeats, was first discovered in bacteria infected with bacteriophages. When used in the laboratory, it allows researchers to manipulate any genomic sequence of their choosing in higher organisms. In the work described in the Cell paper, researchers created a RNA molecule called a guide RNA that carried a sequence of their choice. The investigators then introduced that guide RNA into the cell along with a special bacterial endonuclease. The guide RNA hybridized with the native gene in the monkey genome; the endonuclease found its way to that gene and chewed the DNA. That way, the target gene was disrupted.
The CRISPR system had been used to make transgenic rats, mice and fruit flies. But it hadn’t been used in primates. Huang, Ji, Sha and colleagues were the first to demonstrate that CRISPR does work in our evolutionarily related cousins. In particular, the investigators worked with cynomolgus monkeys because the monkeys are readily available and are small. The females have a similar menstrual cycle to humans and reproduce easily.
To demonstrate the proof of concept, Huang, Ji, Sha and colleagues targeted three different types of genes and showed that they could engineer monkeys that were modified for each gene type. There weren’t any obvious off-target effects. The investigators were even able to get monkeys that carried several modifications at once.
This kind of targeted gene manipulation in monkeys is important for developing better animal models of human diseases. “Monkeys are considered one of the best models for psychiatric related disorders, metabolic function, immunology and so on,” notes Huang. “Monkeys have similar complex neural circuits that do not exist in other simpler organisms, so transgenic monkeys are good for study on cognition, learning, memory and even brain diseases.”
Huang says the next critical step is to see if the genetically modified monkeys can pass along the modifications to their offspring.
