Hua Hua. CREDIT: Qiang Sun and Mu-ming Poo, Chinese Academy of Sciences

EXPERT REACTION: First monkeys cloned using technique that brought us Dolly the sheep

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The first cloned monkeys made using the technique that gave us Dolly the sheep - known as somatic cell nuclear transfer (SCNT) - were born recently, according to Chinese scientists. Zhong Zhong and Hua Hua, two genetically identical long-tailed macaques, were born eight and six weeks ago respectively, say the researchers. Although they're not the world's first cloned monkeys, these are the first to be born using SCNT, which has proved tricky to apply in primates. Previous cloned monkeys were created using a much simpler technique. Successful monkey cloning will allow labs to make populations of genetically identical monkeys, which should help in medical research. SCNT involves removing the nucleus from an egg cell and replacing it with a nucleus from another animal's body cell. The reconstructed egg then develops into a clone of the animal that donated the replacement nucleus.

Journal/conference: Cell

DOI: 10.1016/j.cell.2018.01.020

Organisation/s: Chinese Academy of Sciences, China

Funder: Chinese Academy of Sciences, Key Technology Talent Program, Shanghai Municipal Government Bureau of Science and Technology and National Postdoctoral Program for Innovative Talents.

Media Release

From: Cell Press

Meet Zhong Zhong and Hua Hua, the first monkey clones produced by method that made Dolly

The first primate clones made by somatic cell nuclear transfer are two genetically identical long-tailed macaques born recently at the Chinese Academy of Sciences Institute of Neuroscience in Shanghai. Researchers named the newborns Zhong Zhong and Hua Hua--born eight and six weeks ago, respectively--after the Chinese adjective "Zhonghua," which means Chinese nation or people. The technical milestone, presented January 24 in the journal Cell, makes it a realistic possibility for labs to conduct research with customizable populations of genetically uniform monkeys.

"There are a lot of questions about primate biology that can be studied by having this additional model," says senior author Qiang Sun, Director of the Nonhuman Primate Research Facility at the Chinese Academy of Sciences Institute of Neuroscience. "You can produce cloned monkeys with the same genetic background except the gene you manipulated. This will generate real models not just for genetically based brain diseases, but also cancer, immune, or metabolic disorders and allow us to test the efficacy of the drugs for these conditions before clinical use."

Zhong Zhong and Hua Hua are not the first primate clones--the title goes to Tetra, a rhesus monkey born in 1999 through a simpler method called embryo splitting (Chan et al., Science 287, 317-319). This approach is how twins arise naturally but can only generate up to four offspring at a time. Zhong Zhong and Hua Hua are the product of somatic cell nuclear transfer (SCNT), the technique used to create Dolly the sheep over 20 years ago, in which researchers remove the nucleus from an egg cell and replace it with another nucleus from differentiated body cells. This reconstructed egg then develops into a clone of whatever donated the replacement nucleus.

Differentiated monkey cell nuclei, compared to other mammals such as mice or cows, have proven resistant to SCNT. Sun and his colleagues overcame this challenge primarily by introducing epigenetic modulators after the nuclear transfer that switch on or off the genes that are inhibiting embryo development. The researchers found their success rate increased by transferring nuclei taken from fetal differentiated cells, such as fibroblasts, a cell type in the connective tissue. Zhong Zhong and Hua Hua are clones of the same macaque fetal fibroblasts. Adult donor cells were also used, but those clones only lived for a few hours after birth.

"We tried several different methods, but only one worked," says Sun. "There was much failure before we found a way to successfully clone a monkey."

The first author Zhen Liu, a postdoctoral fellow, spent three years practicing and optimizing the SCNT procedure. He tested various methods to quickly and precisely remove the nuclear materials from the egg cell and promote the fusion of the nucleus-donor cell and enucleated egg. With the additional help of epigenetic modulators that re-activate the suppressed genes in the differentiated nucleus, he was able to achieve much higher rates of normal embryo development and pregnancy in the surrogate female monkeys.

"The SCNT procedure is rather delicate, so the faster you do it, the less damage to the egg you have, and Dr. Liu has a green thumb for doing this," says Muming Poo, a co-author on the study who directs the Institute of Neuroscience of CAS Center for Excellence in Brain Science and Intelligence Technology and helps to supervise the project. "It takes a lot of practice. Not everybody can do the enucleation and cell fusion process quickly and precisely, and it is likely that the optimization of transfer procedure greatly helped us to achieve this success."

The researchers plan to continue improving the technique, which will also benefit from future work in other labs, and monitoring Zhong Zhong and Hua Hua for their physical and intellectual development. The babies are currently bottle fed and are growing normally compared to monkeys their age. The group is also expecting more macaque clones to be born over the coming months.

The lab is following strict international guidelines for animal research set by the US National Institutes of Health, but Sun and Poo encourage the scientific community to discuss what should or should not be acceptable practices when it comes to cloning of non-human primates. "We are very aware that future research using non-human primates anywhere in the world depends on scientists following very strict ethical standards," Poo says.


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Expert Reaction

These comments have been collated by the Science Media Centre to provide a variety of expert perspectives on this issue. Feel free to use these quotes in your stories. Views expressed are the personal opinions of the experts named. They do not represent the views of the SMC or any other organisation unless specifically stated.

Associate Professor James Bourne is a Group Leader and NHMRC Senior Fellow at the Australian Regenerative Medicine Institute at Monash University

Nonhuman primate research remains vital to the continuation of medical research and advances in human health.

The recent description of a protocol to clone macaque monkeys by somatic cell nuclear transfer could be an important tool in medical research for understanding disease in a species genetically more comparable to humans.

While this is the first description of the technology, there were significant limitations, not least given the low efficiency of generating viable offspring.

Therefore, further work needs to be undertaken in order to understand the benefit of this approach, and the ethical implications of its use carefully considered, to ensure that it is only employed when no other alternative model is available.

Last updated: 25 Jan 2018 10:27am

Dr Richard Fry is CEO of Clone International Pty Ltd, an Australasian based company that specialises in the cloning of agricultural animals using somatic cell nuclear transfer.

Cloning by somatic cell nuclear transfer (SCNT) has been achieved in around 23 mammalian species using a range of donor cells.

The most difficult part is to reprogram a differentiated cell donated from the animal to be cloned back to an embryonic cell where it can then develop normally into a live healthy offspring.

It is generally easier to reprogram less differentiated cells taken from a foetus, than from an adult animal, and this is what has been achieved for the first time by the Chinese scientists in the macaque monkey, which to date has been very difficult to clone. They made significant improvements in the efficiency of SCNT in the monkey and achieved live, apparently normal offspring with foetal cells, but not when using adult cells.

This does demonstrate that the technology of SCNT is improving over time in the primate due to a better understanding of the mechanisms at play.

The implications are that cloning by SCNT will one day be possible using cells from an adult monkey to generate clones of identical genomic DNA (but different mitochondrial DNA). The authors suggest that this will provide an excellent model for research into human medicine, particularly the understanding of disease and genetic defects.

The public will consider this one step closer to the production of cloned humans, however this is outlawed across the world, as are a number of other practices that are acceptable in animals.

Last updated: 25 Jan 2018 10:26am

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    Hua Hua

    Hua Hua is one of two genetically identical long-tailed macaques cloned using the technique that brought us Dolly the sheep - somatic cell nuclear transfer.

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    Attribution: Qiang Sun and Mu-ming Poo

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