A monkey in an American laboratory escaped during transportation. Why do clinical trials have to pass the "monkey test" first?

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Written by reporter Li Li Edited by Ji Jingjing

Interview experts:

Chen Ceshi (Director and researcher of the Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Chinese Academy of Sciences, winner of the National Outstanding Young Scientist Fund)

According to the People's Daily Overseas Edition, on the afternoon of the 21st, a truck carrying 100 monkeys to a laboratory in Pennsylvania, the United States, had a traffic accident. Four monkeys escaped, three of which were quickly recovered, and one was still missing. On the evening of the 22nd, the police announced that the escaped monkeys had been found. The US Centers for Disease Control and Prevention said that three monkeys had been euthanized, but did not explain the reason.

The monkeys came from Mauritius, an African country, and were originally to be transported to a quarantine facility designated by the U.S. Centers for Disease Control and Prevention. However, the location of the laboratory and the type of research the monkeys were to undergo were not officially announced. It is reported that monkeys can carry monkeypox virus and monkey B virus, and there have been cases of transmission to humans.

For a time, animal experiments became a hot topic of public concern. Many people also asked questions: What is animal experimentation? Why do animals need to participate in clinical trials? Can animals really simulate human diseases? Let's take a look at the experts' interpretation.

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 monkeys.

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.

New drugs going to clinical trials must first pass the "animal" test

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. Therefore, they have always been a common research subject in the field of medical research, especially in AIDS and aging research.

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.

Modeling challenges: making a group of animals equally ill

Is a new drug effective? To answer this question, we should first test its efficacy on sick animals. How to make animals sick? It doesn't sound difficult. But it is very difficult to make a batch of animals suffer from the same disease with uniform severity and overlapping symptoms. Among them, experimental mice have the characteristics of short life cycle, strong reproductive ability and single genetic background, which means that the experimental cost is relatively low, the experimental data is highly repeatable, and the experimental consistency is also high.

"Due to individual differences in macaques' genetic background and other factors, modeling is very difficult." Chen Ceshi introduced that when selecting experimental macaques, researchers will try to minimize the differences in genetic background, such as choosing individuals of the same gender, age group, region or group, and when building disease animal models, ensure that the experimental environment, conditions and drug dosages are strictly the same.

However, scientists are already on the way to solving this problem. At the end of 2017, the world's first somatic cell cloned macaques "Zhong Zhong" and "Hua Hua" were born at the Institute of Neuroscience of the Chinese Academy of Sciences. The research team of these two cloned monkeys said: The preparation of cloned monkeys is not for curiosity, nor for cloning humans, but to establish animal models of non-human primate diseases, bringing hope for studying the mechanisms of human diseases and drug development.

According to the researchers' idea, with the help of cloning monkey technology, researchers can obtain multiple disease model macaque individuals with the same genetic background in a short period of time (one year). These cloned monkeys with specific disease characteristics and the same genetic background can help scientists quickly test the safety and effectiveness of specific drugs and therapies in primates.

Chen Ceshi is looking forward to this. He believes that cloned monkeys that eliminate individual differences will be very beneficial for building animal models and can ensure experimental consistency to a certain extent. However, the cost is still relatively high and the efficiency is relatively low.

However, with the advancement of science and technology, everything is possible. In the future, as the corresponding cloning technology matures, we will rely on advanced technical means such as cloned monkey disease models to bring hope to more human diseases, especially neurological diseases.

Animal experiments must adhere to the "3R" principle

When it comes to experimental animals, many people may think that using animals for experiments is somewhat cruel, and animal experiments are bound to encounter controversy. However, it must be admitted that at this stage, even though scientists have been working hard to study new methods to replace experimental animals, animal experiments are still irreplaceable in many studies, such as safety testing of new drugs, conquering cancer, cloning and regeneration of organs, etc.

Chen Ceshi said that model animals have made great contributions to human health, so we are always grateful in our work. We have always adhered to the "3R" principle. "3R" is the initials of the three English words "Replace", "Reduce" and "Refine". "Replacement" means using non-animal in vitro methods as much as possible, or replacing live animals with insensate experimental materials, or replacing higher animals with lower animals. "Reduce" means reducing the number of live animals used as much as possible without replacement, improving the utilization rate of experimental animals, and reducing unnecessary repeated experiments. "Refine" means creating a good experimental environment for animals as much as possible or reducing the pain and anxiety caused to animals. For example: let the monkeys watch TV, let them play on the swing, and install heating in their living places in winter. The Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) will conduct a comprehensive review of the facilities provided by relevant institutions for experimental animals and the welfare of experimental animals every three years and issue certificates.

Animals also have lives, so overall, model animals have made great sacrifices for the benefit of humans. April 24th of each year is "World Laboratory Animal Day".

Abroad, all universities and research institutes that use experimental animals for teaching and scientific research activities hold regular memorial ceremonies for experimental animals every year to commemorate the experimental animals that have sacrificed their lives for the cause of human health.

▲The "Monument to the Dead" in the Model Animal Research Institute of Wuhan University (Photo from the Internet)

Many medical schools in China will build a tombstone for experimental animals to commemorate the animals that died. In the courtyard of the Model Animal Research Institute of Wuhan University, this "comfort monument" records the war without gunpowder.

The front of the stone tablet is engraved with "Dedicated to the experimental animals who sacrificed their lives for human health", and the inscription on the back also states "In particular, the 38 rhesus monkeys who sacrificed their lives for the research of anti-SARS vaccines and drugs."

Animal models of last resort:

It cannot truly simulate human diseases

Scientists already have the ability to knock out or insert specific genes in a variety of animals in the laboratory. However, can animal models really simulate human diseases?

According to Science and Technology Daily, Elias Zelhoney, who served as director of the National Institutes of Health (NIH) in 2013, once said: "We have strayed too far from humans in studying human diseases. It can be said that the design of various animal models through transgenic technology has played no role in drug research. We should correct this idea and focus on developing new solutions to understand the biology related to human diseases by studying humans themselves."

In 2016, Joseph Garner, a professor at Stanford University School of Medicine, once again raised a warning in an interview with New Scientist magazine. He believed that medical research is now completely on the wrong track, and very few drugs in clinical trials can eventually be marketed to treat and save lives. One important reason is that animal models cannot truly simulate human diseases. Moreover, very few therapies that have shown obvious effects in animal studies are also applicable to humans.

Some scholars also believe that this approach, which relies heavily on animal models, puts drug development in an embarrassing situation of "spending more money but achieving fewer results."

Another problem is that the simplified standards set by research management departments for experimental animals in order to make it easier to control various factors have become a major disadvantage. The fact is that humans are not static. Even if the living environment and eating habits are similar, people are not exactly the same at different times. Moreover, animals in disease models cannot always follow a simple standard. These standards have made animal research increasingly off track.

In fact, the scientific community has been aware of the dangers of over-standardization for decades. As early as 1935, the famous mathematical biologist Ronald Fisher pointed out in his monograph "Experimental Design": "Specific standards for experimental conditions are often advocated as a panacea, but in order to meet the very narrow range of conditions required by standardization, the experimental results can often only provide a single piece of information, which will become a major disadvantage in actual experiments and lead to failure.

In response to this, Chen Ceshi said that since reality does not allow people to conduct experiments directly, they are indeed facing the above embarrassment.

Although using animal models for research is in a dilemma, it is undeniable that from the history of human drug development, model animals are still an important "hub" that cannot be avoided in linking basic research with clinical practice.

Produced by: Science Central Kitchen

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

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