Hua Hua, one of the first monkey clones made by somatic cell nuclear transfer. [Qiang Sun and Mu-ming Poo / Chinese Academy of Sciences]
Hua Hua, one of the first monkey clones made by somatic cell nuclear transfer. [Qiang Sun and Mu-ming Poo / Chinese Academy of Sciences]

Researchers at the Chinese Academy of Sciences Institute of Neuroscience in Shanghai have published details of the first primate clones made by somatic cell nuclear transfer (SCNT).

The development is expected to help labs someday feasibly conduct research with customizable populations of genetically uniform monkeys—and follows years in which researchers have retreated from research using primates, a development facilitated in the case of chimpanzees by the NIH.

The newborn primate clones are not expected, at least for now, to rekindle the debate over cloning heard two decades ago, when the same technique led to the creation of Dolly the Sheep, born in 1996.

The newborn monkey clones—two genetically identical long-tailed macaques born at the Institute—are named Zhong Zhong and Hua Hua. Their names come from “Zhonghua,” a Chinese adjective that means Chinese nation or people. Zhong Zhong is 8 weeks old; Hua Hua, 6 weeks old.

Zhong Zhong and Hua Hua are not the first-ever primate clones. That distinction is held by Tetra, a rhesus monkey born in 1999 through embryo splitting.

Instead of using embryo splitting, Dr. Sun and colleagues applied SCNT, removing the nucleus from an egg cell and replaced it with another nucleus from differentiated body cells. The reconstructed egg was developed into a clone of the donor of the replacement nucleus.

Details of the accomplishment were disclosed in “Cloning of macaque monkeys by somatic cell nuclear transfer,” published yesterday in the journal Cell by Qiang Sun, Ph.D., director of the Institute’s Nonhuman Primate Research Facility, and colleagues.

“There are a lot of questions about primate biology that can be studied by having this additional model. You can produce cloned monkeys with the same genetic background except the gene you manipulated,” Dr. Sun said in a statement.

“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, the first monkey clones created by somatic cell nuclear transfer. [Qiang Sun and Mu-ming Poo / Chinese Academy of Sciences]

‘An Important Breakthrough’

Research into other diseases will also benefit, Jane Taylor, Ph.D., lecturer at the Biomedical Teaching Organization, Edinburgh Medical School, Biomedical Sciences, University of Edinburgh, told GEN.

“This is an important breakthrough,” said Dr. Taylor, who is also deputy editor of Cellular Reprogramming, a journal published by GEN publisher Mary Ann Liebert, Inc. “The work has significant benefits for medical research, particularly for studying complex neurological disorders such as Alzheimer’s and Parkinson’s disease.”

The use of SCNT to create Dolly touched off a debate over cloning in which the promise of scientific advances has been viewed in conflict with species-altering events feared to cause irreversible harm.

Dr. Taylor said she did not foresee the rekindling of that debate.

“The [SCNT] process, however, is still inefficient and it is currently unknown if the methodology will work in humans,” Dr. Taylor said. “I do not believe this research will lead to cloning a human as there is no value or scientific benefit in doing so. This is not the purpose of the research.”

Dr. Sun and Mu-Ming Poo, Ph.D., a co-author of the study who helped supervise the research, insist that their lab has followed international guidelines for animal research set by the NIH.

“We are very aware that future research using non-human primates anywhere in the world depends on scientists following very strict ethical standards,” said Dr. Poo, director of the Institute of Neuroscience of CAS Center for Excellence in Brain Science and Intelligence Technology.

For one category of non-human primates, chimpanzees, the NIH between 2011 and 2015 gradually ended funding for invasive research and retired the use of the animals in studies, moving them to sanctuaries, following recommendations by the Institute of Medicine (IOM) and National Research Council of the National Academies.

But as the NIH noted in its 2015 announcement, its decisions applied only to chimps: “Research with other non-human primates will continue to be valued, supported, and conducted by the NIH.”

Overcoming SCNT Challenge

Unlike with other mammals, such as cows or mice, differentiated monkey cell nuclei had proven resistant to SCNT until now. Dr. Sun and colleagues overcame the challenge primarily by introducing epigenetic modulators designed to switch on or off the genes inhibiting embryo development following the nuclear transfer.

The researchers found their success rate increased after they transferred nuclei taken from fetal differentiated cells, such as fibroblasts. 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,” Dr. Sun added. “There was much failure before we found a way to successfully clone a monkey.”

Using epigenetic modulators to re-activate the suppressed genes in the differentiated nucleus, one colleague of Dr. Sun—Zhen Liu, Ph.D., a postdoctoral fellow and the study’s first author—achieved much higher rates of normal embryo development and pregnancy in 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,” added Dr. Poo. “It is likely that the optimization of transfer procedure greatly helped us to achieve this success.”

Dr. Sun and colleagues said they expect more macaque clones to be born in coming months. The researchers plan to continue improving the technique, and monitor Zhong Zhong and Hua Hua during their physical and intellectual development. The babies are currently bottle fed and are growing normally compared to monkeys their age.

The research was funded through grants from Chinese Academy of Sciences, the CAS Key Technology Talent Program, the Shanghai Municipal Government Bureau of Science and Technology, the National Postdoctoral Program for Innovative Talents and the China Postdoctoral Science Foundation.

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