China is positioning itself as a world leader in primate research.
April 20, 2016
An
hour's drive from Kunming in southwestern China, past red clay embankments and
sprawling forests, lies an unusual zoo. Inside the gated compound is a quiet,
idyllic campus; a series of grey, cement animal houses stack up on the lush
hillside, each with a clear plastic roof to let in the light. This is the
Yunnan Key Laboratory of Primate Biomedical Research, and its inhabitants are
some 1,500 monkeys, all bred for research.
The
serenity of the facility belies the bustle of activity within. Since it opened
in 2011, this place has quickly become a Mecca for cutting-edge primate
research, producing valuable disease models and seminal publications that have
made its director, Ji Weizhi, a sought-after collaborator. Its campus houses a
collection of gene-edited monkeys that serve as models of Duchenne muscular
dystrophy, autism
and Parkinson's disease. Ji plans to double the number of group leaders working
there from 10 to 20 in the next 3 years, and to seek more international
collaborations — he already works with scientists in Europe and the United
States. “In terms of a technology platform, Ji is just way ahead,” says one
collaborator, cardiologist Kenneth Chien at the Karolinska Institute in
Stockholm.
Ji is
not alone in his ambitions for monkey research. With support from central and
local governments, high-tech primate facilities have sprung up in Shenzhen,
Hangzhou, Suzhou and Guangzhou over the past decade. Last month, the science
ministry approved the launch of a facility at the Kunming Institute of Zoology
that is expected to cost millions of dollars to build. These centres can
provide scientists with monkeys in large numbers, and offer high-quality animal
care and cutting-edge equipment with little red tape. A major brain project,
expected to be announced in China soon, will focus much of its efforts on using
monkeys to study disease.
Many
have since sought refuge for their experiments in China by securing
collaborators or setting up their own laboratories there. Some of the Chinese
centres are even advertising themselves as primate-research hubs where
scientists can fly in to take advantage of the latest tools, such as gene
editing and advanced imaging. “It could be like CERN in Switzerland, where they
set up a large facility and then people come from all over the world to get
data,” says Stefan Treue, a neuroscientist who heads the German Primate Center
in Göttingen, Germany.
“China
will become the place where all therapeutic strategies have to be validated.”
With
China fast becoming a global centre for primate research, some scientists fear
that it could hasten the atrophy of such science in the West and lead to a near
monopoly, in which researchers become over-reliant on one country for essential
disease research and drug testing. “Governments and politicians don't see this,
but we face a huge risk,” says Erwan Bezard, who researches Parkinson's disease
at the French national biomedical research institute INSERM in Bordeaux, and
has set up his own primate-research company, Motac, in Beijing. Europe and the
United States still have the lead in primate research, he says, but this could
change as expertise migrates eastwards. “China will become the place where all
therapeutic strategies will have to be validated. Do we want that? Or do we
want to stay in control?”
Simian
similarities
For
decades, researchers have relied on monkeys to shed light on brain function and
brain disease because of their similarity to humans. Growth in neuroscience
research has increased demand, and although high costs and long reproductive
cycles have limited the use of these animals in the past, new reproductive
technologies and genetic-engineering techniques such as CRISPR–Cas9 are
helping researchers to overcome these drawbacks, making monkeys a more
efficient experimental tool.
China
has an abundance of macaques — the mainstay of non-human-primate scientific
research. Although the population of wild rhesus macaques (Macaca mulatta)
has declined, the number of farmed animals has risen. According to data from
the Chinese State Forestry Administration, the number of businesses breeding
macaques for laboratory use rose from 10 to 34 between 2004 and 2013, and the
quota of animals that those companies could sell in China or overseas jumped
from 9,868 to 35,385 over that time. Farm populations of marmosets, another
popular research animal, are also on the rise.
Most
monkeys are shipped to pharmaceutical companies or researchers elsewhere in the
world, but the growing appreciation among scientists of monkey models has
prompted investment by local governments and private companies in dedicated
research colonies. The country's 2011 five-year plan singled out primate
disease models as a national goal; the science ministry followed up by pumping
25 million yuan (US$3.9 million) into the endeavour in 2014.
Scientists
visiting China are generally pleased with the care given to animals in these
facilities, most of which have, or are trying to get, the gold-standard
recognition of animal care — accreditation by AAALAC International.
Ji's
Yunnan Key Laboratory is the most active primate facility, but others are
giving it competition. The new monkey facility at the Kunming Institute of Zoology
was funded as part of the national development scheme for big science equipment
that includes telescopes and supercomputers. The money will help the institute
to double its colony of 2,500 cynomolgus monkeys (Macaca fascicularis)
and rhesus macaques.
Zhao
Xudong, who runs the primate-research facility, says that the plan is to “set
it up like a hospital, with separate departments for surgery, genetics and
imaging”, and a conveyer belt to move monkeys between departments. There will
be systems for measuring body temperature, heart rate and other physiological
data, all to analyse the characteristics, or 'phenotypes', of animals, many of
which will have had genes altered. “We are calling it the 'genotype versus
phenotype analyser',” says Zhao. It will take ten years to finish, but he hopes
to begin building this year and to start research within three. Other
facilities, although smaller, are also expanding and diversifying. The
Institute of Neuroscience in Shanghai plans to increase its population of 600 Old
World monkeys to 800 next year and expand its 300-strong marmoset colony.
A
question of cost
Outside
China, the numbers are heading in the opposite direction. Harvard Medical
School closed its affiliated primate facility in May 2015 for 'strategic' reasons.
Last December, the US National Institutes of Health decided to phase out
non-human-primate experiments at one of its labs and subsequently announced
that it would review all non-human-primate research that it funds. In Europe,
researchers say, the climate is also growing colder for such research.
Costs
are a major disincentive. In 2008, Li Xiao-Jiang, a geneticist at Emory
University in Atlanta, Georgia, helped to create the world's first transgenic
monkey model of Huntington's disease1 with colleagues at Yerkes
National Primate Research Centre. But Li says that it costs $6,000 to buy a
monkey in the United States, and $20 per day to keep it, whereas the
corresponding figures in China are $1,000 and $5 per day. “Because the cost is
higher, you have to write a bigger grant, and then the bar will be higher when
they judge it,” says Li. Funding agencies “really do not encourage large-animal
research”.
For Li,
the solution was simple: go to China. He now has a joint position at the
Institute of Genetics and Developmental Biology in Beijing, where he has access
to around 3,000 cynomolgus monkeys at a farm in Guangzhou and some 400 rhesus
monkeys at the Chinese Academy of Medical Sciences' monkey facility in Beijing.
He has churned out a series of publications on monkeys with modified versions
of the genes involved in Duchenne muscular dystrophy2 and
Parkinson's disease3.
Neuroscientist
Anna Wang Roe says that red tape drove her to China. Roe's team at Vanderbilt
University in Nashville, Tennessee, is attempting to work out how modules in
the brain are connected, and she estimates that she and her colleagues have
spent 25% of their time and a good deal of cash documenting the dosage and
delivery-method for each drug they administered to their monkeys, as required
by regulations. “We record something every 15 minutes,” she says. “It's not
that it's wrong. It's just enormously time-consuming.”
In
2013, impressed by the collaborative atmosphere at Zhejiang University in
Hangzhou, she proposed that it build a neuroscience institute. The next day the
university agreed, and she soon had a $25-million, 5-year budget. “Once the
decision is made, you can start writing cheques,” she says. She is now closing
her US laboratory to be the director of the Zhejiang Interdisciplinary
Institute of Neuroscience and Technology, where she hopes to open a suite of
the latest brain-analysis tools, including a powerful new 7-tesla functional
magnetic resonance imaging device that she says will give images of the primate
brain at unprecedented resolution.
“This
place just makes things happen quickly.”
Bob
Desimone was similarly impressed with the speed at which China moves. As a
neuroscientist who heads the McGovern Institute for Brain Research at the
Massachusetts Institute of Technology in Cambridge, in January 2014, he had a
'meet and greet' with the mayor of Shenzhen. In March, the mayor donated a
building on the Shenzhen Institute of Advanced Technology campus for a
monkey-research facility, and the centre's soon-to-be director, Liping Zhang,
promised that it would be ready by summer. Thinking that impossible, Desimone
bet two bottles of China's prized mind-numbing liquor, maotai, that it
wouldn't be done in time. He lost. The group raised most of the $10 million
needed from city development grants, along with a small input from McGovern,
and soon the first animals were being installed in the Brain Cognition and
Brain Disorder Research Institute. “This place just makes things happen
quickly,” Desimone says.
But
money and monkeys alone are not enough to lead to discovery. Researchers say
that China is short on talented scientists to take advantage of the
opportunities provided by animal research. That's why the organizers of the
country's new primate centres hope to attract an influx of foreigners to
permanent posts or as collaborators. So far, many of those moving to China have
been Chinese or foreigners with a previous connection to the country, but
others are expressing interest, says neuroscientist Guoping Feng, also at the
McGovern Institute. Already, the Shenzhen primate centre has recruited from
Europe and the United States, and Desimone says that it will be “an open
technology base. Anyone who wants to work with monkeys can come.”
Edited
monkeys
Already,
competition is fierce as researchers are racing for the low-hanging fruit —
engineering genes with established roles in human disease or development.
Almost all reports of gene-edited monkeys produced with these techniques have
come from China. Desimone predicts that the pursuit of monkey disease models
“could give China a unique niche to occupy in neuroscience”.
The
cages of Ji's facility are already full of the products of gene editing. One
troop of animals has had a mutation
genetically engineered into the MECP2 gene, which has been
identified as the culprit in humans with Rett's syndrome, an autism spectrum
disorder. An animal sits listless and unresponsive, holding tight to the bars
of the cage as her normal twin sister crawls all over her. In another cage, a
monkey with the mutation pumps its arm, reminiscent of repetitive behaviour
seen in the human disorder. Some incessantly suck their thumbs. “I've never
seen that in a monkey before — never so constant,” says Ji.
Among
the range of other disease models in Ji's menagerie are monkey versions of
cardiovascular disease, which he is working on in collaboration with the
Karolinska Institute. And last year, Ji made the world's first chimeric monkeys
using embryonic stem cells4, an advance that could make the
production of genetically modified animals even easier. The question now is
whether these genetically modified monkeys will propel understanding of human
brain function and dysfunction to a higher level. “You can't just knock out one
gene and be sure you'll have human-like disease phenotype,” says Ji.
Researchers
see an opportunity to understand human evolution as well as disease. Su Bing, a
geneticist at the Kunming Institute of Zoology, is working with Ji to engineer
monkeys that carry the human version of a gene called SRGAP2, which is
thought to endow the human brain with processing power by allowing the
growth of connections between neurons. Su also plans to use
CRISPR–Cas9 to introduce human versions of MCPH1, a gene related to
brain size, and the human FOXP2 gene, which is thought to give humans
unique language ability. “I don't think the monkey will all of a sudden start
speaking, but will have some behavioural change,” predicts Su.
International
divide
Although
the opportunities are great, there are still obstacles for scientists who
choose to locate their animal research in China. Trying to keep a foot in two
places can be challenging, says Grégoire Courtine, a spinal-cord-injury
researcher based at the Swiss Federal Institute of Technology in Lausanne, who
travels almost monthly to China to pursue his monkey research at Motac. He has
even flown to Beijing, done a couple of operations on his experimental monkeys,
then returned that night. “I'm 40 years old, I have energy in my body. But you
need to really will it,” he says.
Another
downside, says Li, is that policies can change suddenly in China. “There is
uncertainty. That makes us hesitate to commit,” says Li, who has retained his
post at Emory University. And the immunity that China's primate researchers have
had to animal-rights activism could start to erode, warns Deborah Cao, who
researches law at Griffith University in Brisbane, Australia, and last year
published a book on the use of animals in China5. People are
starting to use Chinese social-media sites to voice outrage at the abuse of
animals, Cao says.
China
has competition in its bid to dominate primate research, too. Japan has
launched its own brain project focused on
the marmoset as a model: the animal reaches sexual maturity in a
year and a half, less than half the time it takes a macaque. Some research
facilities in China are now building marmoset research colonies — but Japan is
considered to be several years ahead.
And
some researchers want to ensure that such work continues outside Asia. Courtine
says that he's “fighting to keep alive” a monkey-research programme he has at
Fribourg, Switzerland, because he thinks it's important to have a division of
labour. “Research that requires quantity, I'll do in China. I would like to do
sophisticated work in Fribourg,” he says.
Back at
his primate centre in Yunnan, Ji is sure that such work is already taking
place. His dream, he says is “to have an animal like a tool” for biomedical
discovery. He knows there is a lot of competition in this field, especially in
China. But he feels confident: “The field is wide, and there are many, many
projects we can do.”
http://www.nature.com/news/monkey-kingdom-1.19762
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