China cloning advance to cut monkey use in research, say scientists

Critics appear not to have read either the Chinese scientific journal reports or media release about them clear to the end

SHANGHAI, China––Had the Institute of Neuroscience at the Chinese Academy of Sciences in Shanghai put the last three lines of a January 24,  2019 media release announcing the births of five cloned monkeys at the top instead of the bottom,  the response from animal advocates and ethicists around the globe,  ranging from hostile to hysterical,  might have been worlds different.

“The research will help to reduce the amount of macaque monkeys currently used in biomedical research around the world,”  explained Institute of Neuroscience director Mu-ming Poo in the next-to-last sentence of the media release.

“Much smaller number may be sufficient”

The bottom line,  for Mu-ming Poo,  was that “Without the interference of genetic background,”  which the cloning technique bypasses,  “a much smaller number of cloned monkeys carrying disease phenotypes may be sufficient for pre-clinical tests of the efficacy of therapeutics.”

That translates,  “Much less use of nonhuman primates in drug safety testing,”  which most animal advocates and ethicists should welcome,  even if preferring no use of nonhuman primates at all.

The third-from-last line of the Institute of Neuroscience media release stated that the Chinese Academy of Sciences “is following strict international guidelines for animal research.”

Presumably Mu-ming Poo meant not the 33-year-old current U.S. standards,  but rather the much stricter European Union standards adopted in 2010,  as well as applicable Chinese standards updated in 2003,  2006,  and 2015.

Challenge to breeding industry

Probably,  though,  Mu-ming Poo and the Institute of Neuroscience at the Chinese Academy of Sciences preferred to downplay the challenge their work presents to the Chinese macaque breeding industry.

In recent years Chinese breeders have exported 18,000 to 19,000 macaques to laboratories around the world each year,  about 11,000 of them to labs in the U.S.,  or a little more than twice as many are bred within the U.S.

If the trend in macaque breeding follows the trend in mouse and rat breeding since commercial production of genetically modified rodents began with OncoMouse in 1988,  lab demand for large numbers of conventionally bred animals will rapidly yield to demand for far more expensive,  but also more useful cloned animals,  of whom far fewer will be needed per experiment.

Transgenic monkeys bred in U.S. since 2000

Instead of highlighting the potential of their accomplishment for transforming the laboratory monkey supply industry,  however,  Mu-ming Poo and team emphasized their scientific breakthrough,  the nature of which was subsequently much misunderstood and misreported by mass media.

Transgenic monkeys genetically modified to better model human disease have been produced in the U.S. since October 2000,  when a genetically modified rhesus macaque named ANDi (DNA spelled backward) was born in Beaverton,  Oregon,  at the Oregon Regional Primate Research Center.

Transgenic marmosets were introduced in 2009 by the Central Institute for Experimental Animals in Kawasaki,  Japan.

Thousands of genetically modified macaques and marmosets have been born since then,  including at U.S. facilities.

Dolly the sheep

What Mu-ming Poo et al achieved was an advance beyond the procedure used to produce the cloned baby macaques Zhong Zhong and Hua Hua in January 2018,  using essentially the same technology,  called somatic cell nuclear transfer,  that the Roslin Institute in Scotland used to clone Dolly the sheep (1996-2003).

Cloning primates proved to be much more difficult than cloning sheep.

“Scientists have ‘cloned’ primates by splitting an embryo in half,  but the process is essentially just artificial twinning rather than true cloning,”  explained Telegraph science editor Sarah Knapton when Zhong Zhong and Hua Hua were born.

Added South China Morning Post writer Stephen Chen,  “For decades, researchers around the world had struggled to achieve [true cloning] because some proteins were easily damaged in the cloning process.  The damaged proteins affected chromosomes’ ability to divide,  which meant the fetus always died at the later stage of development.  This continued until last year’s breakthrough,  which used technology that remains a secret.”

Cloning combined with genetic modification

The next step in refining the production of nonhuman primates who have been specifically modified for laboratory use,  after developing “true cloning,”  was to combine cloning with genetic modification,  so that far fewer animals would have to be bred to produce an experimental cohort with identical characteristics.

“Using cloned monkeys would allow researchers to give them different doses of the same drug and then precisely measure the effects,”  wrote Chen.

Combining true cloning with genetic modification is what Mu-ming Poo et al did,  and described doing in two articles published in the January 24,  2019 edition of the Chinese journal National Science Review.

Brave New World?

The scientific language of the articles,  to non-scientists,  tended to evoke imagery from the 1931 Aldous Huxley novel Brave New World,  especially since Shenzen biologist He Jiankui in November 2018 announced that he had produced the world’s first genetically edited human babies,  a pair of twin girls,  using a technology abbreviated as CRISPR.

Summarized Financial Times writer Tom Hancock and Shanghai correspondent Wang Xueqiao,  “Chinese researchers carried out the first CRISPR editing on monkeys in 2014,  used the technique to create the world’s first gene-edited human embryos in 2015,  and in 2017 were the first to use it on viable human embryos, capable of developing into babies.

Scientist busted

“A regulation from China’s science ministry in 2003 banned the implantation of altered human embryos for reproductive purposes,”  Hancock and Wang Xueqiao added,  “and says altered embryos should not be developed beyond 14 days.”

But He Jiankui allegedly forged documents showing that his use of CRISPR to produce the twin girls had cleared a required review by a hospital ethics committee.  He Jiankui is now facing criminal charges,  while Chinese president Xi Jinping has called for stricter regulation of CRISPR experiments.

Meanwhile in Shanghai,  Mu-ming Poo and team produced “The first cohort of five gene-edited monkey clones made from fibroblasts of a monkey with disease phenotypes,”  they explained, by muting “the expression of BMAL1,  a core circadian regulatory transcription factor,  in the [gene] donor monkey using CRISPR/Cas9-mediated gene editing at the embryo stage.”

Bypassed aborted fetus

“In the previous work,”  clarified the Institute of Neuroscience media release,  the cloned monkeys ZhongZhong and Hua Hua “were generated by using fibroblasts from an aborted fetus. The present work succeeded in using fibroblasts from a young adult gene-edited donor monkey with disease phenotypes.”

This procedure,  Mu-ming Poo et al said,  “demonstrates that a population of customized gene-edited macaque monkeys with uniform genetic background will soon be available for biomedical research.”

How are the five new cloned monkeys different,  and why are they valuable?

Losing sleep

“These monkeys exhibit a wide range of circadian disorder phenotypes, including reduced sleep time,  elevated night-time locomotive activities, dampened circadian cycling of blood hormones,  increased anxiety and depression,  as well as schizophrenia-like behaviors,”  summarized the Institute of Neuroscience media release.

Said senior Institute of Neuroscience researcher Hung-Chun Chang,  “Disorder of circadian rhythm could lead to many human diseases,  including sleep disorders,  diabetic mellitus,  cancer,  and neurodegenerative diseases.  Our BMAL1-knock out monkeys thus could be used to study the disease pathogenesis as well as therapeutic treatments.”

Agreed Qiang Sun,  director of the Nonhuman Primate Research Facility at the Institute of Neuroscience,  “We believe that this approach of cloning gene-edited monkeys could be used to generate a variety of monkey models for gene-based diseases,  including many brain diseases,  as well as immune and metabolic disorders and cancer.”

Only five of 300 embryos developed

“Sun’s team injected the nucleus from a genetically altered adult male [somatic cell] into an egg and planted the fertilized embryo in the womb of a surrogate mother,”  described South China Morning Post writer Stephen Chen.  “More than 300 embryos were created this way, but only five fully developed.”

Besides Chen,  Nick Whigham of News.com.au recognized the animal welfare significance of the Institute of Neuroscience achievement.

“Because primates share approximately 95% of human genes and a number of physiological and anatomical similarities,  biomedical research currently uses a large number of monkeys,  sometimes up to 100,000 annually around the globe,”  Whigham said,  considerably understating actual use,  which is that high in Europe alone.

U.S. laboratories currently house about 110,000 monkeys,  of whom about 70% are actually used in any given year.

Monkey use has been climbing

“This number will be greatly reduced by the use of monkeys with uniform genetic background that reduces the noise in experimental studies,”  Mu-ming Poo emphasized.  “This will greatly help the ethical use of non-human primates for biomedical purposes.”

This is no small consideration.

According to USDA Animal & Plant Health Inspection Service data collected under the U.S. Animal Welfare Act,  “Scientists used 75,825 nonhuman primates for research last year,  up 22% since 2015 and 6% since 2008,”  reported Science online editor David Grimm in November 2018.  “In contrast, the number of cats, dogs,  rabbits,  and other animals recorded by USDA are all being used at lower numbers than they were a decade ago,”  though the numbers of mice,  rats,  and birds––believed to be upward of 95% of animal use in U.S. laboratories––are not tracked.

Macaques,   marmosets,  baboons

While the National Institutes of Health quit funding invasive chimpanzee research in 2015,  “Nearly two-thirds of the nonhuman primates the agency supports are rhesus macaques,”  Grimm wrote,  “with cynomolgus macaques (15%),  baboons (6%),  and a dozen other monkey species making up the remainder.  The rising demand for rhesus macaques appears to be driven by researchers studying HIV/AIDS,  the brain,  Alzheimer’s disease,  and addiction,  according to an NIH report released in September 2018.”

Demand for marmosets has increased to the point that “the number of U.S. marmoset research colonies jumped from eight in 2009 to 27 today,”  reported Kelly Servick of Science Now in October 2018.

The Institute of Neuroscience at the Chinese Academy of Sciences could help to reverse that trend.

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