Last updated February 1, 2018 at 11:38 am
The first primate clones using the same technique used to clone Dolly the sheep have been born in China.
The pair of long-tailed macaques were born recently a few weeks apart at the Chinese Academy of Sciences Institute of Neuroscience in Shanghai.
The two genetically identical monkeys, named Zhong Zhong and Hua Hua (from the Chinese “Zhonghua” which means Chinese nation or people) were created using somatic cell nucelar transfer (SCNT).
Cloning monkeys is difficult
Some might argue that ‘Tetra’ was technically the first cloned rhesus monkey back in 1999, produced using an embryo-splitting model.
But when we think of cloning now, most people refer to the SCNT method used on Dolly, which takes the nucleus out of an egg cell and replaces it with the nucleus of an adult cell, to produce clones genetically identical to the adult donor.
Since the first mammal clone back in 1997, scientists have struggled to clone primates.
Successfully cloned monkey embryonic stem cells using SCNT were produced a decade ago, but until now successfully reprogramming and transplanting a cloned non-human primate embryo had failed to produce a living monkey.
Compared to other mammals, reprogramming a monkey cell nucleus has proved the stumbling block.
Epigenetics plays a role
In this new study, Qiang Sun and his colleagues added epigenetic modulators targeting “reprogramming resistant regions” that switch on or off genes involved in embryo development.
Treatment of a combination of these modulators at the one-cell stage improved the development of blastocysts (the stage at which the embryo must reach before it can implant in the uterus), and the pregnancy rate for transplanted embryos.
“We tried several different methods, but only one worked,” says Qiang Sun, Director of the Nonhuman Primate Research Fcility at the Chinese Academy of Sciences Institute of Neuroscience.
“There was much failure before we found a way to successfully clone a monkey”.
In the experiment cells were cloned either from foetal or adult monkey cells, using a technically exacting process. More than 250 cloned embryos were created to end up with two surviving young being born.
Cloning from adult cells was the least successful approach – 181 cloned embryos reached blastocyst stage. But from 22 confirmed pregnancies, only two carried to term.
Cloning from foetal cells
These two monkeys both died (three and 30 hours after birth) due to respiratory failure.
Researchers speculate that this is could be because reprogramming adult cells is not as efficient as reprogramming fetal cells, or that there are differences in the cell types used.
“It may just be a matter of numbers,” says Qiang Sun. “If we produced more embryos maybe a healthy baby will be born. So we have female surrogates pregnant now with foetuses derived from adult cells that seems to be developing well.”
The group had more success cloning from foetal cells with 70 embryos cloned from them that reached blastocyst stage implanted into 21 female monkeys.
Six confirmed pregnancies resulted in the two live births of Zhong Zhong and Hua Hua, born 58 and 28 days ago respectively.
The young macaques are still being hand-reared, and live together in a human baby incubator. They will be monitored to check for any long-term health consequences.
As genetically identical clones, who have the same environment and eat the same food and play with the same toys, researchers will be doing regular brain scans and following their nervous system development which will allow them to see what role environmental ‘noise’ plays in producing variation in each monkey.
Zhong-Zhong, one of the cloned macaque monkeys. Credit: Qiang Sun and Muming Poo Chinese Academy of Sciences
Why clone monkeys at all?
The researchers state their primary reason for cloning monkeys is to create disease models for medical research.
Around 12 million animals are used each year in scientific procedures in the EU, and among these, around 10,000 are non-human primates.
Monkeys are much more closely related to humans, and so can be good models for understanding disease and developing new treatments. They have some brain areas common with humans that just don’t exist in rats and mice, for example.
Monkeys also share many features of their reproductive physiology that are unique to primates.
In the past, primate research has been essential for advances in deep-brain stimulation used to treat Parkinson’s, treatment of premature babies, kidney dialysis and drugs to treat asthma.
The macaques cloned in this study are the most commonly used monkeys used by medical researchers around the world.
Qiang Sun hopes that through cloning, the number of animals needed for experiments will be greatly reduced. Cloning produces genetically identical individuals, reducing the variation between animals.
While other methods of drug testing are important and provide useful information, Qiang Sun is skeptical that cell culture or computer modelling will ever fully replace animal testing.
“I’m personally not confident we can produce really good medical treatments without testing on real animals,” he says.
Producing a clone is the first step for this research group. The next step is to produce a genetically-edited monkey that will be used to investigate a specific disease.
The first the researchers will try is likely to be Parkinson’s Disease.
“It’s probably the easiest and most quick to do,” says Muming Poo, a co-author of the study.
“The drug-induced lesions model is not a very good one. All drug companies are currently using this model, but it has symptoms not like human disease.”
The group hopes in the future to develop other models for diseases such as Alzheimer’s and autism.
Ethical issues
If the thought of cloning monkeys simply to make medical test subjects leaves you feeling squeamish, you’re not the only one.
The creation of cloned animals for use in medical research raises many ethical questions. The trend of use of non-human primates in Europe and the US has been downwards in recent years, reflecting community attitudes towards animal experimentation and also the cost of doing research using these models.
Between 2008 and 2011, the number of monkeys used in research in Europe declined by 28%.
Many researchers argue that we now have ways to replace the use of primates in research using techniques like cell and tissue engineering and sophisticated non-invasive imaging on human volunteers.
There have also been issues in the past about controversial cloning of dogs for medical research in China, and concerns about the lack of legal and regulatory protections for lab animals.
China implemented a set of national guidelines for animal research in 2016. The current study was carried out following the regulations set by the US National Institute of Health.
What does this mean for cloning humans?
Now that the technical barrier has been broken for primate cloning, in principle human cloning could now be feasible. Although the researchers point out that is not the reason for their current research.
“There’s no intention for us to apply this method to humans” says Qiang Sun. “There must be an international discussion on this issue, just like we’re now starting to discuss the ethical issues around artificial intelligence.”
This research is published in Cell.
Related content:
Epigenetics reveals possible DNA regions associated with autism
CRISPR and Human Embryos
Education Resource:
First cloned primates produced in China
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