Researchers around the world interested in unravelling the mechanisms of complex human disorders, such as Alzheimer’s disease, could soon have access to cloned monkeys with genomes that have been edited to display these conditions in China.
On 24 January, scientists at the Institute of Neuroscience (ION) in Shanghai reported that they had used gene-editing to disable a gene in macaque monkeys (Macaca fascicularis) that is crucial to their sleep–wake cycle. The scientists then cloned one of those monkeys to produce five primates with almost identical genes1,2.
It is the first time that researchers have cloned a gene-edited monkey and proof of principle for the researchers’ plan to create populations of genetically identical primates that they say will revolutionize biomedical research. Some of the researchers are part of the new International Centre for Primate Brain Research, which has the goal of creating such populations and received government funding in November.
“This certainly is a research tool that is unexplored and there may be many possibilities for innovative uses,” says Mitchell Lazar, who studies metabolic disease at the University of Pennsylvania in Philadelphia. New monkey models of diseases such as sickle cell anaemia and cystic fibrosis “would be incredibly helpful to allow humanity to treat or cure these illnesses”, he says.
Primates are the best animal model for studying higher cognitive functions and brain disorders in humans, says neuroscientist Mu-ming Poo, ION’s director and co-founder of the new 720 million yuan (US$106 million) centre. Researchers around the world have edited the genomes of monkeys to create models of diseases, such as Huntington’s disease and severe immune disorders. A group at the ION have also disabled a gene in monkeys that is linked to autistic behaviour in people. It was also the first to clone primates, two identical macaque monkeys, last year.
But primates are expensive, and many people object to them being used in research. The advantage of creating cloned monkeys is that it reduces the number of animals needed for certain types of experiments, such as testing whether a drug works, says Poo. Researchers typically need large numbers of animals to determine whether the effects they see are because of the drug or due to genetic variation among the animals. By using genetically identical animals, such uncertainty can be eliminated, reducing the number of animals required, he says.
Poo, who hopes to recruit about half of its research staff from outside China, is planning to first create models of brain diseases, such as Alzheimer’s disease, Parkinson’s disease, a severe genetic intellectual disability called Angelman syndrome and several genetic eye disorders. As the symptoms of these disorders appear slowly, Poo says it will useful to have animal models on which scientists can monitor the progression of these diseases.
Over the next few years, Poo plans to work with international researchers to also create primate models of metabolic and immune-deficiency disorders and cancer that scientists could experiment on in China.
In Europe and the US, non-human-primate research increasingly faces regulatory hurdles, costs and bioethical opposition. This stands in contrast to China; the country's 2011 five-year plan set primate disease models as a national goal. The science ministry followed up by investing 25 million yuan (US$3.9 million) into the endeavour in 2014.
Slow and expensive
At the moment, the process of cloning monkeys is inefficient and expensive. To create the 5 cloned macaques, the team started with 325 cloned gene-edited embryos, which they implanted into 65 surrogate monkeys. The process cost about $500,000, estimates Poo.
The team used the standard cloning technique, the same process used to clone Dolly the sheep. In this method, the DNA of a donor cell – in this case taken from an adult monkey whose genome had been edited – is injected into an egg that has had its own genetic material removed. The DNA reprograms into an embryonic state, from which specialized cells can form.
Poo’s team is the first to clone primates using DNA from adult cells. The two macaques the group cloned last year came from fetal DNA. The success with adult DNA means that the group can check the gene edits they made to embryos have resulted in the desirable traits in an adult monkeys before they decide to clone them.
That monkeys can be cloned from other living monkeys is an exciting proof of principle, says reproductive biologist Shoukhrat Mitalipov, from the Oregon Health and Sciences University in Portland. Mitalipov expects that the costs of cloning primates will come down, and that they will probably be a good model for researchers to study genetic diseases. “It was the same thing with all the agricultural cloning of cattle and pigs, at first the efficiencies were really low, and it was expensive,” says Mitalipov. “Now people do it just like they do IVF,” he says.
But some bioethicists and scientists think that experiments using monkeys should be a last resort because of their higher levels of cognition. Lazar says that some experiments in mice – for example, research into the genes behind human diseases – “are equally appropriate scientifically” as in primates. Research in mice is also more accepted by the public, and the animals are cheaper and quicker to produce. Lazar worries that if scientists have ready access to populations of gene-edited monkeys, they might use them for experiments when rodents would do.
Poo says that mice are not a good substitute for studying higher cognitive functions and brain disorders in humans. He argues that cloning will reduce the burden on monkeys by cutting the number used in labs. The ION follows strict international guidelines for animal research, he says.
On 24 January, the People for the Ethical Treatment of Animals (PETA), an animal rights group based in Norfolk, Virginia, issued a statement, saying that ION’s experiments were “a monstrous practice that causes [the monkeys] to suffer”.
Poo’s team will continue to study the effect of gene editing on their five cloned macaques. The group disabled a gene, BMAL1, that has a crucial role in maintaining circadian rhythm, the internal clock that facilitates a healthy sleep–wake cycle. In people, BMAL1 mutations have been linked to diabetes, hypertension and depression.
The monkeys with the disabled BMAL1 genes move more at night and sleep less overall, hallmarks of circadian-rhythm disorders, says Chang Hung-Chun, a specialist in circadian rhythm at the ION. They also display psychosis-related symptoms, such as fear and anxiety, when put in unfamiliar environments. “These results demonstrated that circadian disruption can be a major trigger to psychiatric disorders [in monkeys],” says Chang.
The team’s next step is to look in detail at the neural mechanisms that might create these problems. It will also take advantage of the genetically identical monkeys to hunt for diagnostic markers of circadian rhythm-related disorders and possible therapies.
Poo published the research on circadian rhythms in a journal of which he is executive editor in chief – National Science Review. He said he did this because the journal needs publicity. "The papers were thoroughly reviewed by four international experts. It was processed by [the journal's] life sciences editor, I was not involved," he says.
Nature 566, 15-16 (2019)