The new coronavirus is spreading around the world. Everyone wants to know, where does this virus come from? The job of finding the source of a disease-causing virus is called “virus tracing.”
“This is not just to satisfy curiosity, but more importantly, it is of great significance to the prevention and treatment of infectious diseases. Only by finding the source of the virus and understanding how the pathogen develops into a virus that causes disease to humans can we answer whether the virus will recur, That is, whether everyone cares about whether it will make a comeback, “said Zhao Guoping, an academician of the Chinese Academy of Sciences and a researcher at the Shanghai Academy of Life Sciences, Chinese Academy of Sciences, in an interview with a reporter from the Science and Technology Daily.
However, although scientists around the world are struggling to explore, it seems that the origin of the new coronavirus is still confusing. “In fact, not only the new coronavirus, but many diseases in human history, such as AIDS, SARS, etc., although great progress has been made in the exploration of its source, the tracing of the virus itself is a scientific problem and very complicated. It takes a long time and there is uncertainty. “
Traceability based on scientific evidence to find pathogens must meet Koch’s law
“For the tracing of unknown pathogenic viruses, there are at least two steps: the first step is to find the pathogenic pathogen; the second step is to determine which animal was the first to be infected (or is the natural carrier), that is, the natural host of the virus At this step, we also need to explore the process and mechanism of the virus from the natural host to infect people, and then spread from person to person. “Zhao Guoping said.
Zhao Guoping said that the traceability of the virus requires evidence, which is the process of scientific proof. There are two main types of evidence, one type is biological evidence, including etiology, clinical medicine, and epidemiology. Its advantage is “real world” imaging, but there may be human interference during the acquisition process. , And the difficulty of the experimental process; the other type is molecular biological evidence, including genome sequencing, antibody detection, etc. Its advantage is “exact”, but it is not so easy to establish contact with biological evidence.
To find pathogens, Koch ’s law needs to be met. Wu Guizhen, a researcher at the Institute for Viral Disease Control and Prevention of the Chinese Center for Disease Control and Prevention, introduced that Koch ’s rule was proposed by German bacteriologist Robert Koch. It refers to the determination of a virus as a pathogenic microorganism that requires four criteria: The same microorganisms are present in the human body and do not exist in healthy people; such microorganisms should be isolated from the host and cultured purely in the culture medium; use a pure culture of this microorganism to inoculate a healthy and sensitive host with the same disease It will happen repeatedly; this microorganism can be isolated and cultured again from the host of the experimental disease.
When SARS broke out, two teams at Erasmus University Rotterdam in the Netherlands used this rule to determine that SARS-CoV was the cause of SARS. They used SARS-CoV to infect crab-eating macaque monkeys, and showed symptoms similar to human infection with SARS-CoV. The virus isolated from the infected monkey was the same as the virus at the time of the initial vaccination. SARS-CoV was detected in the infected monkey. Specific seroconversion.
However, Wu Guizhen said that finding the pathogen is only the first step in tracing the source. Whether the Chinese chrysanthemum bat is the only natural host of SARS, and how the virus it carries mutates into the virus carried by the raccoon dog needs further study.
“It takes a long time to find pathogens in full accordance with Koch ’s law. In today ’s era, molecular biology methods such as seroconversion and gene sequencing are required to speed up the identification of suspected pathogens: what species they belong to, whether they are unrecognized New species, etc. From the perspective of the whole process of tracing, the information evidence obtained by the two major technologies of biology and molecular biology will eventually converge into a chain and verify each other, which is the real completion of the task.
“Patient Zero” is the key to the traceability and the difficulty
“Generally speaking, there are two paths for virus tracing, one is epidemiological investigation, and the other is virus distribution investigation in animals and the environment.” Said Zhao Wei, director of the Third Level Laboratory of Biosafety of Southern Medical University.
Zhao Wei said that the epidemiological investigation of the traceability of general infectious diseases started from the contact history of the first discovered patient, that is, to find the “patient No. 0”, but this search work can be more difficult.
Taking AIDS as an example, from October 1980 to May 1981, five young people who were very healthy in Los Angeles in the United States developed Pneumocystis carinii pneumonia. It will appear in people with severely weakened immune function. The condition of five young people deteriorated rapidly, and two people had died when reported. This is the earliest AIDS patient discovered, but at that time it was speculated that this disease has spread in the world for a long time.
Eight years later, a study in 1988 found an earlier American patient. When the researchers tested a tissue sample left by a 15-year-old named Robert Rayford in 1968, the results showed HIV positive. After another 10 years, in 1998, scientists found a blood sample from 1959 in Kinshasa, Congo, and found that it contained HIV-1. This is the earliest AIDS “patient zero” that can be traced back to now. But is he really the “zero” number?
Secondly, the investigation of virus distribution in animals and the environment is the most direct and important method. Zhao Wei said that if scientists discovered that primates in southern Cameroon in Africa had a virus similar to HIV, SIV, that is, monkey immunodeficiency virus. Therefore, some scientists put forward the theory of “injured hunter”, that is, an injured hunter who was exposed to the virus in the primate was the first to be infected. Ebola hemorrhagic fever, one of the most dangerous infectious diseases in modern times, is currently believed by most scientists to be derived from fruit bats, because there are different types of fruit bats that can carry this virus throughout central Sahara and southern Africa.
In recent years, bioinformatics technology has developed rapidly. Scientists can determine the genetic relationship and transmission process between different virus strains through gene homology comparison, and even calculate the origin time of a certain virus through “molecular clock theory”. But in terms of traceability, these cannot replace traditional epidemiological investigations.
In Zhao Guoping’s view, tracing the source of a new virus from a natural source is like a criminal police cracking a case. When the criminal police arrived at the crime scene, they first collected evidence, and then conducted various investigations to form various hypotheses; shun vines, rule out and find new evidence and new clues, and finally find the suspect. At the same time, the suspect confessed the criminal process, and identified the first scene of the crime and the hiding place of the crime tool, and confirmed each other with the evidence obtained. Problems in any of these links may have no results.
Traceability is difficult, everyone should have reasonable expectations
Viruses are very cunning, especially viruses whose genes are composed of ribonucleic acid (RNA) instead of deoxyribonucleic acid (DNA), are more prone to mutation, and the degree of mutation is higher and faster.
Zhao Guoping said that coronavirus is a more cunning RNA virus. Its genome is relatively large (three times the size of the HIV virus genome), and it is also prone to mutations including large fragments such as deletions and recombination; of course, most of the mutations are unfavorable for the growth and reproduction of the virus. It was naturally eliminated in the process.
Zhao Guoping believes that in the process of cross-species transmission, the virus needs to accumulate those mutations that adapt to the new host (human) to form a “transmissive clone” that spreads among the population, that is, the virus strains that have been repeatedly tested and sequenced and spread to all parts of the world . However, most of the mutations in this early accumulation process have no obvious “phenotype” of human infection, and the probability of being found is naturally very low; but this is the “scientific evidence” required for traceability. .
Taking SARS as an example, Zhao Guoping explained that scientists have been looking for the source after the outbreak. In 2005, scientists discovered SARS-like coronavirus in three bats, but the genome sequence was too different from the SARS coronavirus genome. Until 2015, the SARS-like coronavirus was found in Chinese chrysanthemum bats, with 96% similarity to the human SARS coronavirus genome sequence, and the S protein amino acid sequence similarity to the human cell receptor ACE2 reached 97%, Only to basically reveal the natural host of SARS coronavirus.
“Virus tracing is extremely difficult and contains many uncontrollable factors. Some evidence is lost and may never be found. In many cases, it is impossible to connect the chain completely. Some are not necessarily clear through long-term research, only To form an inference, more is to find nodal evidence. For this, everyone should have a reasonable expectation.