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2021-05-11 09:46:21

Since last year, Zhang Wen has been receiving more and more calls from new business contacts looking to buy monkeys and beagles for scientific experiments. But as his regular customers had already placed orders ahead of time and supplies have been dwindling, he’s frequently had to disappoint the inquirers.

“There aren’t any left — they’re all sold out,” Zhang, chairman of Jiangsu Johnsen Bioresource Co. Ltd, responded to the second cold call in less than an hour before a recent interview.

The COVID-19 pandemic has caused supply problems in many industries over the past year. In part due to the global race to develop vaccines, however, few resources have become so desperately sought-after as monkeys.

Before any new drug can reach the market, one of the first steps they must pass is safety tests conducted on animals. Monkeys are one of the main types of lab animals used in such experiments, because they are biologically similar to humans. Monkeys are also used for basic research into areas such as viruses, diseases, and neurology, as well as cutting-edge biology research into areas like stem cells and gene editing. They can answer fundamental research questions that research on rodents has failed to address.

Zhao Shengli, secretary of the China Laboratory Primate Breeding and Development Association (CLPBADA), explained that the price of lab monkeys has soared from 15,000 yuan (then $2,280) per monkey in late 2016 to the current 62,000 yuan ($9,600) — and prices can jump from week to week. “Monkeys are hard to find right now, or to be more exact, there aren’t any available even if you can afford the high prices,” he said.

A staff member holds a lab monkey’s paw at a hospital in Xi’an, Shaanxi province, June 2020. Shao Rui/Xinhua

A staff member holds a lab monkey’s paw at a hospital in Xi’an, Shaanxi province, June 2020. Shao Rui/Xinhua

Pricey primates

Strict requirements for animals ensure research quality but also lengthen their supply cycle, making it difficult to quickly ramp up production. Regulations state that every lab monkey must have detailed genetic and health records, and that only second-generation human-reared monkeys and their offspring can be used for experiments and research. Given the five years until a monkey reaches sexual maturity, it takes about eight years until a new batch of “commercial monkeys” is ready for use, with production relatively stable afterward. “That’s why the supply of lab monkeys is tight at the moment, and will be for the next three to five years,” Zhao said.

The two main types of lab monkeys are the rhesus macaque and crab-eating macaque, the latter also known as the long-tailed macaque or cynomolgus monkey. Between these two species, there are more than 240,000 such monkeys in captivity in China, according to Zhang Yuchao, CLPBADA secretary-general. But when excluding infants and individuals used for breeding, the actual stock of commercial monkeys stands at around 100,000. After subtracting the monkeys to be sold overseas, as well as those considered too old, domestic stocks stand at only around 30,000, with many of those already off the market.

Basic research requires around 5,000 monkeys annually, but the largest demand is for use in preclinical trials of new drugs, with approximately 25,000 monkeys — mainly crab-eating macaques — needed each year. There is no fixed number of monkeys needed to run a preclinical trial on a new drug. Toxicology tests, which administer repeat doses over 28 days, require 40 monkeys on average. If additional tests such as for drug metabolization are also to be carried out, they will need another 20 or so monkeys. One lab animal is generally used for only one experiment.

Monkeys aren’t just expensive to purchase, using them for experiments also comes with other costs. Wang Xiaohua, chief physician of the Department of Anesthesiology at Xuanwu Hospital of Capital Medical University, explained that central government-approved projects requiring the use of monkeys generally cost at least 10 million yuan. Nearly one-third of this sum is used for modeling lab monkeys — breeding animals with desirable traits for particular experiments. Outside the research period, the monkeys are taken care of in specialized institutions. In total, the cost of purchasing and caring for each monkey can reach up to 100,000 yuan.

“The main cost comes from hiring professional staff,” said Li Qin, chief scientist at CLPBADA. “Veterinarians act as spokespeople for laboratory animals, interpreting their behaviors to ensure both the quality of the research and the welfare of the animals.” He gave an example of trembling in mice. When a mouse trembles and its ears are standing up, that means it’s excited. When its whiskers are trembling and pointed backward, that means it’s cold. If its whiskers are horizontal, then it’s in pain. Professional vets have to make numerous observations throughout the day during the course of an experiment, and are charged per observation, with rates ranging up to the thousands of yuan.

Three young rhesus monkeys in a cage at the New England Regional Primate Research Centre, Harvard Medical School, Massachusetts, U.S. IC

Three young rhesus monkeys in a cage at the New England Regional Primate Research Centre, Harvard Medical School, Massachusetts, U.S. IC

Supply issues

Even before the COVID-19 pandemic spurred vaccine research, the biomedical industry’s rapid development caused a global rise in the use of lab monkeys. According to industry reports, the number of applications to China’s National Medical Products Administration for new drug clinical trials increased from 494 in 2014 to 983 in 2019. Accordingly, the number of lab monkeys sold and used in China grew from 7,000-8,000 in 2013, to almost 30,000 in 2019, said Li. But this increase in production was not achieved sustainably.

Globally, the United States uses more monkeys in research than any other country, reaching a record high of more than 74,000 in 2017. The U.S. once relied heavily on India for supplies of rhesus monkeys, but India stopped exporting to the country in 1978 for various reasons that ranged from religious issues to concerns over animal protection. Crab-eating macaques from Southeast Asia then became the new go-to monkey for the United States. Taking advantage of low wages and the opportunities presented by the policies of “reform and opening-up” at the time, China’s monkey industry quickly stepped in to replace Southeast Asia and became the world’s largest supplier of nonhuman primates for laboratory experiments.

China has an abundance of nonhuman primates, with 45 subspecies spread across the country — approximately 10% of the world’s total. However, foreign crab-eating macaques, not the native rhesus macaques, have come to dominate the market for lab monkeys in China. The reason, Li explained, is “because the vast majority of monkeys used in preclinical trials overseas were crab-eating macaques.” Because of their small size, they use fewer resources, which lowers costs and also means they tend to be favored in follow-up studies.

The earliest business of China’s lab monkey industry was foreign trade, so there has always been a high proportion of crab-eating macaques, followed by rhesus monkeys at around 15% to 20%. Other species are rarely used. Zhang Wen’s company is the only one in China that sells marmosets, trading 200-300 annually. The fourth most popular species, the African green monkey, is only used by a select few research institutions in China. According to conservative estimates, there are around 48 sizable lab monkey breeding facilities in China. At current market rates, a single facility can sell for more than 1 billion yuan.

The financial crisis of 2008 affected the main business of China’s lab monkey industry — exporting the animals to other countries. For a time, it was difficult to find buyers, but the country’s lab monkey population continued to grow and reached a peak of nearly 300,000 in 2013. It was against this backdrop that China stopped importing monkeys for breeding.

After reforms in 2015, China accelerated the approval process for new medicines, and domestic research and development for new drugs took off. This in turn increased demand for monkeys and steadily depleted the country’s stocks. The suspension on importing monkeys meant for several years that some breeding facilities, wanting to cash in on the favorable market, sold off their breeding monkeys.

In addition, a lack of selective breeding means that domestic breeding facilities have struggled with aging populations and low fertility rates, with production capacity unable to keep up with demand. Crab-eating macaques imported from Southeast Asia have thus remained crucial. It wasn’t until the end of 2018 when China specifically granted special import applications for some breeding facilities. However, the COVID-19 pandemic saw the situation take another turn for the worse.

On Jan. 26, 2020, in response to the coronavirus outbreak, the Chinese government announced a prohibition of wildlife trade, which required places breeding wild animals to be isolated, and for wild animals to not be sold or transported. As such, the import and export of lab monkeys in China ground to a halt.

Researchers give a lab monkey a checkup in Guangzhou, Guangdong province, 2013. Liu Dawei/Xinhua

Researchers give a lab monkey a checkup in Guangzhou, Guangdong province, 2013. Liu Dawei/Xinhua

All in all, more monkeys are being sold than produced. “The production capacity of the two main species of lab monkeys has started to decline, from a total annual output of around 40,000 in the past, to 30,000-35,000 in 2020,” said Li, the scientist. “The combined annual total for exports and domestic sales is 40,000-50,000. In a few years, the stockpiles will be completely used up.” Although imports and exports are suspended, monkeys already preordered by overseas companies cannot be released on the domestic market, he explained, meaning domestic supply remains strained.

A senior industry insider pointed out that by suspending lab monkey exports, China is actually forcing foreign customers to turn to Southeast Asia. Once companies in the region gain access to capital and mature technology, the area’s production of lab monkeys is likely to overtake China in a few years. Then, it will be hard for China’s lab monkeys to reenter the international market. More concerning is whether breeding facilities and other local interests in places where the animals are native will try to have monkey exports to China restricted. In that case, China will end up shooting itself in the foot. “It’s for that reason we’re currently calling for the lifting of restrictions on imports,” said Zhang Yuchao, the CLPBADA secretary-general.

Domestically, the industry also has its problems to overcome. The CLPBADA has proposed various measures to prevent monkey inbreeding, such as through exchanges between breeding facilities, and has urged enterprises to improve the level of monkey selection, conservation, and breeding.

Strategic reserves

With more monkeys being used for preclinical trials of new drugs in China, there are fewer and fewer available for basic research. “We should distinguish market demand from scientific research and national demand of monkeys, to ensure there are enough lab monkeys for basic research,” said Ji Weizhi, director of Kunming University of Science and Technology’s Institute of Primate Translational Medicine. Since 2015, he has been submitting proposals to the authorities calling to establish a national nonhuman primate research center.

Zhao, the CLPBADA secretary, said the shortage of monkeys since 2018 gradually drove up prices until they became unaffordable for academic research institutions. Researchers often tell the CLPBADA: “We can’t afford to buy monkeys.” To safeguard their own supplies, some big pharmaceutical firms have acquired, merged with, or established their own breeding facilities, buying 6-month-old and 1-year-old monkeys to keep for later use.

Earlier this year, Ren Jin, director of the Center for Drug Safety Evaluation & Research at the Shanghai Institute of Materia Medica under the Chinese Academy of Sciences (CAS), told the media that 90% of China’s lab monkeys are owned by private enterprises. She suggested that allocating the animals should be included in the government’s resource allocation plan, prioritizing the needs of national strategic projects.

Lab monkeys in cages in Wuhan, Hubei province. From the website of the Center for Animal Experiment/Animal Biosafety Level-III Laboratory

Lab monkeys in cages in Wuhan, Hubei province. From the website of the Center for Animal Experiment/Animal Biosafety Level-III Laboratory

At present, the only national resource center for nonhuman primates in China is the Kunming Primate Research Center at the Kunming Institute of Zoology, CAS, which has 3,000 to 4,000 monkeys. However, these monkeys are not used for market circulation, and the center’s main task is species conservation.

The United States recognized the strategic importance of lab monkeys as far back as 2002. The National Institutes of Health funds seven national primate research centers, which house around 35,000 nonhuman primates, including 25,000 lab monkeys primarily used for basic research. In addition, the U.S. imports more than 30,000 primates a year to meet industrial demand.

As for how to develop China’s strategic monkey reserves, an expert with the CLPBADA who asked not to be named, said: “China should look to its own national conditions — it doesn’t need to copy the experience of the United States.” The expert added that in the long term, rather than simply selling animals as resources, China’s technical expertise regarding laboratory animals should be improved, including developing new research breeds so as to avoid overreliance on foreign intellectual property.

However, developing models for lab monkeys is no simple matter. Zhang Wen explained that, as higher animals, monkeys have much more complex gene expressions than mice, for example, which makes it difficult to stably produce generations of animals with the same desired genetic traits. Even if it was possible to build an intergenerational model, the lifecycle of monkeys means that it would take at least a decade, if not several.

China has thus specially directed some of its funding programs for scientific research on “laboratory animals.” This includes conducting research into creating animal models for human diseases, improving the service quality of research centers, and developing key technologies for evaluating lab animal quality. Over the next five years, 100 million yuan will be doled out annually to support the program.

In January 2018, a team led by Sun Qiang of the CAS’s Institute of Neuroscience successfully created the world’s first monkeys cloned using somatic cell nuclear transfer. Sun said that cloning technology can be used to create a large number of monkeys with identical genetic backgrounds, which would not only meet the urgent needs for research into brain diseases and higher cognitive functions, but could also be widely used to test new drugs. “This really is a new direction, but we’re a long way off from using them for safety evaluation,” a senior industry insider said, adding that the technology for cloning monkeys is not yet widespread and costs are currently far above the market price.

A researcher holds a baby marmoset at the New England Regional Primate Research Centre, Harvard Medical School, Massachusetts, U.S. IC

A researcher holds a baby marmoset at the New England Regional Primate Research Centre, Harvard Medical School, Massachusetts, U.S. IC

The new virus

From Jan. 26 to June 29, 2020, CLPBADA coordinated 3,551 lab monkeys from its members for basic research into the newly discovered coronavirus. “Scientific research units already had limited numbers of monkeys, and the trade in commercial monkeys was banned during the epidemic period,” said Zhang Yuchao, the CLPBADA secretary-general. “At that time, the Ministry of Science and Technology would only discuss approving the trade of monkeys in breeding facilities if it was related to COVID-19.”

In May 2020, a study titled “Development of an Inactivated Vaccine Candidate for SARS-CoV-2” was published in the journal Science, becoming the world’s first publicly reported results on animal experimental research into the novel coronavirus. The article declared that the vaccine, developed by Sinovac Biotech, was safe and effective. The team’s experiments were conducted on rhesus macaques, as well as mice and rats.

But many other research projects cannot find the animals necessary to conduct them. They are being adjusted or cut to minimize animal demand, said Niu Yuyu, deputy director of Kunming University of Science and Technology’s Institute of Primate Translational Medicine. “There simply aren’t enough monkeys if all the research questions are to be properly addressed.”

A version of this article was originally published by China Newsweek. It has been translated and edited for length and clarity, and is republished here with permission.

Translator: David Ball; editors: Ye Ruolin and Kevin Schoenmakers.

(Header image: A monkey plays with a face mask in Malaysia, Oct. 30, 2020. Mohd Rasfan/AFP/People Visual)