The price of experimental monkeys has soared 20 times! Why is it so hard to find a monkey now?

The price of experimental monkeys has risen from several thousand yuan to 160,000 yuan. For a time, experimental monkeys became the focus of attention. Which monkeys are experimental monkeys? Why is it so difficult to find a monkey now?

Written by Li Peng and Li Li Edited by Ji Jingjing

New Media Editor/Li Yunfeng

Interview experts

Huang Chengming (Researcher, Institute of Zoology, Chinese Academy of Sciences)

Chen Ceshi (Researcher at Kunming Institute of Zoology, Chinese Academy of Sciences, Director and Researcher of Yunnan Key Laboratory of Animal Models and Human Disease Mechanisms)

Recently, the topic #Many leading pharmaceutical companies are frantically hoarding monkeys# has become a hot search. Why have experimental monkeys become the object of acquisition by major pharmaceutical companies?

According to the "Announcement on the Winning Bid for the Procurement of Experimental Crab-eating Monkeys by the China Food and Drug Inspection Institute" published on the Ministry of Finance website in March this year, the China Food and Drug Inspection Institute purchased 30 crab-eating monkeys for a total of 3.66 million yuan, with each crab-eating monkey costing as much as 122,000 yuan. According to media reports, industry insiders said that the current price of crab-eating monkeys has exceeded 160,000 yuan, and some industry insiders also said, "160,000 yuan per monkey is a thing of the past, and the price changes every day."

The supply of experimental monkeys is tight, and their value has soared from 6,567 yuan per monkey in 2014 to more than 160,000 yuan per monkey now, an increase of more than 20 times. Despite this, many research institutions are still facing the situation of "price is not enough for monkeys". Why do animals need to participate in clinical trials? Where does the situation of "scarcity of monkeys" come from?

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Every disease needs a suitable "model"

Nowadays, more and more animals contribute their lives to scientific research and human health development. For example, mice are used in cancer research, pigs are used in organ transplantation, ferrets are used in influenza research, and tree shrews and ducks are used in hepatitis research.

Chen Ceshi said that animals and humans can suffer from various diseases, and some diseases are homologous, that is, animals and humans can suffer from them, such as tumors. Some viruses are transmitted across species, such as AIDS, which was first discovered in chimpanzees and then transmitted to humans. Some viruses are unique to animals, such as the African swine fever virus that was prevalent in China in 2019, which mainly infects pigs but not humans.

▲It is currently known that HIV-1 originates from SIVcpz in chimpanzees and HIVgor in gorillas, while HIV-2 originates from SIVsmm in black-and-white-browed gorillas.

Animal disease models have always been considered a bridge from basic to clinical research. Since the 1980s, foreign countries have already begun to establish gene knockout animal models for new drug research and development. Later, with the improvement of genetic engineering technology, people can use transgenic technology, gene targeting technology or gene recombination technology to further artificially modify, change or intervene in the original DNA genetic composition of organisms, thereby obtaining new strains of experimental animals that are more suitable for specific disease research. Among them, primates are often used in human nervous system research and related drug development because they are closer to humans than mice in terms of cardiovascular and cerebrovascular, metabolism, nervous system and drug metabolism.

At present, the most commonly used model animals in clinical practice are zebrafish, nematodes, fruit flies, mice, rats, macaques, etc. Mice are the most important model animals in medical research, and animal models of many diseases are mouse models.

In addition, as the research on disease mechanisms becomes more in-depth, research on certain diseases, such as infectious diseases, cardiovascular diseases, and neurological diseases, requires larger model animals. Therefore, some model animals with high evolutionary status are increasingly favored by scientific researchers, such as dogs, pigs, tree shrews, and non-primate monkeys.

Therefore, scientists are currently looking for the "best" animal model. What drugs may be effective and what dosage is safe to take all rely on animal models to draw conclusions. Finding a good animal model can really help people find appropriate prevention and treatment methods.

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New drugs must pass the "animal" test before entering clinical trials

Before being approved for human clinical research, all new drugs must first pass safety evaluations on experimental animals (rodents, dogs, and even monkeys) to rule out serious toxic side effects of the drugs, including carcinogenicity, teratogenicity, toxicity, and mutagenicity. Only then can they be used on humans under safe conditions. It can be said that they build a protective wall for human drug safety.

▲New drug development flow chart

When conducting experiments, researchers will choose organisms that are as similar to humans in structure, function, metabolism, etc. as possible based on the type of disease, while also considering the feasibility and economy of practical operations.

Chen Ceshi said that in theory, monkeys are the best model for studying many human diseases. In 2007, an international research team of more than 170 scientists from 35 institutions, the "Macaque Genome Sequencing and Analysis Consortium", sequenced the genome and found that the similarity between macaque genes and chimpanzees and humans is about 97.5%, while the similarity between chimpanzees and humans is even higher, with 99% of the genes shared by the two. Chimpanzees have been listed as protected animals due to their small number. Macaques are also protected animals. In my country, they are listed as Class II national key protected animals.

▲The genetic similarity between macaques and humans is about 97.5%, and they have many similarities in genetics and physiology, so they have always been a common research subject in the field of medical research, especially in AIDS and aging research. (Picture from the Internet)

At the same time, internationally, macaques are listed as CITES Appendix II species, and trade is restricted. However, macaques have the largest distribution range and a large population among living primates. Adult female macaques generally reach sexual maturity at 4-5 years old, and give birth to one baby per year. Macaques have many similarities with humans in genetics and physiology, so they have always been a common research subject in the field of medical research, especially in AIDS and aging research.

"In the past, macaques were rarely used, mainly because of the high cost." Chen Ceshi said that the initial cost of using a monkey for related animal experiments is about 10,000 yuan. The research cycle of using monkeys for experiments is also very long, generally requiring observation for several years to decades. But now great breakthroughs have been made in monkey gene manipulation technology, which can help humans better study various diseases.

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Which monkeys are experimental monkeys?

"The price of experimental monkeys has always been high, and it is impossible for the price to drop in the short term." A staff member surnamed Liu from a company that specializes in acting as an agent for preclinical drug safety evaluation told reporters that the species of experimental animals here include mice, rats, rabbits, dogs, monkeys, etc., and like other experimental animals, when using experimental monkeys, the routes of administration include oral, dermal, intradermal, subcutaneous, intraperitoneal, intramuscular, intravenous, etc., which means that the experiments of a project will use a large number of experimental monkeys, sometimes even more than 20 or 30.

As the name implies, experimental monkeys are monkeys used specifically for experiments. Huang Chengming, a researcher at the Institute of Zoology, Chinese Academy of Sciences, said in an interview that generally speaking, there are two main types of monkeys that can be used for experiments: the first type is various wild monkeys that can survive in the wild and can be used for experimental observations of various animal behaviors and regional distribution, such as the key research subjects, golden monkeys, white-headed langurs, black-headed langurs, etc. The second type is monkeys that are specifically used for projects such as vaccine, drug development experiments, and physiological experiments. Currently, dedicated experimental monkeys are generally macaques.

Macaques are typical macaques, with a stout body, short tail, brown head, brown-grey or brown-yellow back, orange-yellow or orange-red lower body, and light grey-yellow belly. The average body length of an adult is about 50-60 cm. They are widely distributed in the vast areas of southern China, northern India, and some Asian countries such as Afghanistan, Pakistan, Nepal, Myanmar, Vietnam, and Thailand. They mainly live in dense forests or sparse forests on rocky cliffs, valleys beside streams, and banks of rivers. They like to live in groups, often in large groups of more than ten or even hundreds of them.

Huang Chengming said that among all monkeys, macaques are relatively large in number, highly adaptable, easy to domesticate and breed, and physiologically closer to humans, so they are ideal experimental animals in biology, psychology, medicine and other disciplines. Currently, the monkeys commonly used in experiments are mainly rhesus macaques and crab-eating macaques. Among them, rhesus macaques are mainly distributed in my country and India, and crab-eating macaques are mainly distributed in some countries and regions in southeastern Asia, such as Vietnam, Cambodia, Laos, Myanmar, Thailand, Bangladesh, Malaysia, the Philippines, and Indonesia.

However, under the stimulation of economic interests, long-term indiscriminate hunting has also led to the endangerment of macaques. In my country, macaques have been listed as a second-class protected animal in China's "National Key Protected Wildlife List" and a vulnerable species in the "China Red List of Endangered Animals - Mammals". In addition, they are also listed as a low-risk (LC) level in the 2008 Red List of Endangered Species of the "World Conservation Union". In this context, wild macaques are also prohibited from being used in various clinical experiments. "Now almost all macaques used in experiments are artificially bred." Huang Chengming said.

The demand for experimental macaques in medical research is huge. Infectious disease research, pharmacology and toxicology research, reproductive physiology research, oral medicine research, geriatric research, organ transplantation and ophthalmology research, endocrine disease and teratology research, oncology research, etc. are all inseparable from them. In addition, the research and development of new drugs for humans in medicine is extremely cautious. New drugs must first be used on non-primate animals, such as mice and rabbits, and then begin to experiment on primates such as monkeys. Only when experiments on animals such as primates and above prove that there is no harm can clinical trials on humans be carried out, and experiments on primates are the last and most important link. The "National Standard for the Quality of Laboratory Animals in China" promulgated in 2001 also clearly stipulates that all new drug development and disease diagnosis, establishment and improvement of treatment methods, etc. must obtain reliable conclusions obtained on non-human primates before entering clinical research. It is for this reason that relatively easy-to-obtain macaques have become important research animals for many scientific research institutions and large pharmaceutical companies.

In May 2020, the article "Rapid Development of Inactivated Vaccines for SARS-CoV-2 Virus" was published in Science magazine, led by Qin Chuan from the Institute of Medical Laboratory Animals of the Chinese Academy of Medical Sciences. It became the world's first publicly reported animal experimental research results of the new crown vaccine. The article announced that the vaccine developed by Beijing Sinovac Biotech Co., Ltd. is safe and effective. The experiment was conducted on rhesus monkeys.

Since cynomolgus monkeys reproduce quickly and weigh 4-5 kg, which is smaller than the average 7 kg rhesus monkey, the dosage of drugs used is also relatively small. Therefore, since the 1970s, the application of experimental monkeys has been fully turned to cynomolgus monkeys. The experimental monkeys bred in China are mainly cynomolgus monkeys, accounting for about 80%-85% of the total industry. Since cynomolgus monkeys are not native to China, breeding monkeys need to be introduced from Southeast Asia.

Another type of experimental monkey now is the marmoset, also known as the thumb monkey, which is a small non-human primate from the Amazon rainforest in South America. Compared with other non-human primates, the weight of an adult common marmoset is less than 400 grams. It has the advantages of small size, sexual maturity, short gestation period, docile temperament and easy laboratory breeding. It also has strong genetic similarities with humans and has great prospects for medical scientific research. However, there are not many in China and other countries in the world that are specifically raised for experiments.

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China is the world's center for breeding experimental monkeys

Located deep in the mountains at the junction of Anhui and Jiangxi in Qimen County, Xiwu Forest Farm has rows of monkey houses in a huge courtyard, where a large number of macaques are raised. This is the Anhui Experimental Macaque Center. Established in 1999, the center was once affiliated with the local forest farm and mainly engaged in the domestication and breeding of ordinary macaques. After passing the review and acceptance of the National Forestry Department in 2005, the macaques here officially began to be used as experimental monkeys. In the following decade, many medical research institutions, including the Shanghai Branch of the Chinese Academy of Sciences, Anhui Medical University, and Shandong Binzhou Medical College, have selected monkeys from the center for experiments. Every year, dozens or even hundreds of macaques are used for experiments.

Since experimental monkeys are specially used for scientific experiments, their breeding is different from that of ordinary monkeys, and there are many rules in their breeding management. For example, a file is built for each monkey, and the monkey's date of birth, weaning date, who their parents are, as well as illness, treatment and medication will be recorded one by one, so as to provide accurate information for future experiments of scientific researchers. In addition, monkey houses are generally divided into two types: one is the monkey house in the breeding area, which usually houses a male monkey and several female monkeys. In order to meet the requirements of clear pedigrees of non-human primate experimental animals (experimental monkeys), the breeding group of experimental monkeys can only be raised in a single male population. In other words, the "polygamy" system is prevalent in experimental monkeys. Generally speaking, the male-female ratio of macaques and crab-eating macaques in breeding groups is 5-6:1 and 7-8:1 respectively. The reporter learned that in some breeding bases where the number of male monkeys is insufficient, a male monkey can often have more than ten "wives".

The other type is the monkey cages, each of which contains more than a dozen monkeys. When the monkeys grow up, they will form their own families and reproduce. Of course, among these monkeys, if they are not wild monkeys, many of them will become experimental platforms for various drugs, and some will even sacrifice their lives for this.

A staff member of Xiwu Forest Farm in Qimen County told reporters that in the past few years, the state has implemented a system to separate experimental breeding units such as wildlife rescue centers under forestry administrative departments from the activities of domesticating, breeding and operating experimental monkeys. The Anhui Experimental Macaque Center here was sold to a private enterprise in 2015. The changes in the Anhui Experimental Macaque Center are also a reflection of China's entire experimental monkey breeding. At present, 90% of China's experimental monkey breeding is controlled by private enterprises. Guangxi is China's largest experimental monkey breeding base, with more than ten experimental monkey breeding farms. The number of monkeys in stock once reached more than 100,000, accounting for half of the country's breeding. On average, more than 10,000 experimental animals are provided to domestic and foreign countries each year, and the breeding and supply volume are both ranked first in the country.

After years of development, China has now become the world's largest experimental monkey breeding country. However, before the outbreak of the COVID-19 pandemic, China had no control over the number of experimental monkeys exported, which led to a sharp shortage of experimental monkeys in China after the pandemic.

How many experimental monkeys are there in China? According to information disclosed by The Paper, there are only about 30,000 experimental monkeys in China, and the market is increasingly calling for "priceless monkeys".

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As a "strategic resource", experimental monkeys are "hard to come by"

The global demand for experimental monkeys exceeds 100,000 per year, and most of them come from China. Data shows that by 2013, China's export of experimental monkeys had reached about 30,000, occupying a pivotal position in the world's experimental monkey market. Guangxi, as China's largest province for the storage and export of experimental monkeys, accounts for more than 60% of the country's exports. Of the nearly 35,000 monkeys imported by the United States in 2019, 60% came from China.

After the outbreak of the COVID-19 epidemic, China's export of experimental monkeys has changed significantly. On January 26, 2020, the State Administration for Market Regulation and other departments jointly issued the "Notice on the Prohibition of Wildlife Trade", requiring "the quarantine of wildlife breeding sites in various regions, and the strict prohibition of the spread and transfer of wildlife to other countries". China's import and export of experimental monkeys was suspended.

In China, since experimental monkeys are expensive and most institutions do not have the qualifications to raise them, many basic studies do not use experimental monkeys. Instead, they often use non-primates such as rats, mice, and rabbits. Only some institutions use experimental monkeys when they are involved in new drug research. However, major pharmaceutical companies must use experimental monkeys when developing new drugs, and many of them entrust specialized companies to conduct experiments. Whether these companies conducting new drug experiments have sufficient sources of experimental monkeys has become the key to the company's business.

The breeding cycle of experimental monkeys is extremely long. Because it usually takes about 5 years for monkeys to reach sexual maturity from birth, and about 5 and a half months from pregnancy to delivery, it takes at least 8 years for the first batch of second-generation "commercial monkeys" to be released. According to regulations, experimental monkeys can only be used for experiments after they are 3 years old. And usually monkeys only give birth to one baby per litter, and the number of experimental monkeys cannot increase suddenly, which has led to the high price of experimental monkeys in China, and the supply of experimental monkeys will continue to be tight in the next few years.

After the COVID-19 outbreak, the supply of monkeys for scientific research in many domestic R&D institutions has become increasingly scarce. In addition to the skyrocketing prices, the shortage of monkeys has significantly affected the progress of some urgently needed scientific research projects. Some industry insiders believe that China must establish a long-term mechanism for the import, breeding, supply and export management of experimental monkey breeders, so that China will not be in a passive position when it is in urgent need of a large number of experimental monkeys.

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Produced by: Beijing Science and Technology News | Beijing Science and Technology Media

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