Focus on the new coronavirus pneumonia These scientific issues you should be concerned about

Where does this disease come from, where does it go, how to cure it, what experiences and lessons have been learned? It took me two days to read all the papers that had been published. For the new coronavirus pneumonia, talk about a few scientific issues you might care about:

Produced . . . Sina Science and Technology”, Science Everybody

Writing the article Wang Liming Professor, Researcher, Doctoral Mentor, Institute of Life Sciences, Zhejiang University

1. Where does this disease come from and what is the source?

It can now be confirmed that the real culprit behind this new coronavirus pneumonia is a new type of coronavirus (2019-nCoV) that has just been discovered.

Focus on the new coronavirus pneumonia These scientific issues you should be concerned about

This is the third time in the 21st century that members of the coronavirus family have wreaked havoc on the human world. In 2003 and 2012, sars virus (Severe Acute Respiratory Syndrome virus) and MERS virus (MERS virus) suddenly descended on the human world twice, leaving unhealed scars in China and the Middle East.

I have to remind me that it is not particularly easy to identify the pathogenic microorganisms of any new infectious disease. You may intuitively think it’s okay to look at what microbes are in a pneumonia patient’s lungs, but the problem is that most of the time a person has thousands of different kinds of bacteria and viruses in their bodies, so doctors and scientists need to be very careful when determining pathogens. One counterexample you may still remember is that when SARS was endemic in 2003, a scientist (The chief researcher of the China Center for Disease Control and Prevention, Hong Tao, a member of the Chinese Academy of Engineering) mistakenly misjudged a certain chlamydia in the patient’s body as a pathogen, nearly causing a major problem in outbreak management.

And how to judge the pathogen of an infectious disease, there is a very old but effective way: the Koch Law.

This is the standard proposed by the German bacteriologist Koch in 1884 to judge the causal relationship between a pathogen and an infectious disease:

A large number of these pathogens can be found in each patient;

This pathogen can be isolated from the patient’s body and then cultured in vitro;

In vitro cultured pathogens can make healthy people sick;

The same pathogens can still be found in newly sick people.

For more than a hundred years, the Koch rule has been continuously revised, but overall it remains the gold standard for the scientific community as a whole to identify infectious disease pathogens.

Specifically, Chinese scientists detected the presence of the virus in the first dozen patients with the disease using electron microscopes, RT-PCR and high-throughput DNA sequencing (Zhu N et al NEJM 2020; Huang C et al Lancet) 2020), which also successfully isolated the virus particles and demonstrated that they can still infect human epithelial cells in petri dishes (Koch Law 2) (Zhu N et al NEJM 2020). Of course, because there is no animal model of the new coronavirus. Koch’s Law 3 and 4 cannot be directly verified, but scientists have also shown that the virus can successfully infect mice cells by transferring a human ACE2 protein, the new coronavirus receptor in the guessed, mice cells. This conclusion supports, at least in part, the establishment of Koch Law 3 and 4 (Zhou P et al bioRxiv 2020).

In other words, at this point in time, Chinese scientists have proved to the full extent that the new coronavirus is the pathogen of this new pneumonia.

The next question is, where does this pathogen come from?

Focus on the new coronavirus pneumonia These scientific issues you should be concerned about

The first thing to be clear is that although the same coronavirus family, but the new coronavirus is not SARS or its variants, the genetic sequence between the two is only 80%, is quite distant relatives (compared to the human and orangutan genome similarity as high as 98%, human and human similarity is more than 99.9%).

Complete genomic sequence information for the new coronavirus (Wu F et al bioRxiv 2020) has been obtained, and many research groups have compared it to many known coronavirus sequences. Of particular note are two coronaviruses that are naturally parasitic in the body of bats: one that is present in a certain bat body in Zhoushan region with a sequence similarity of nearly 90% (Zhu N et al NEJM 2020); bioRxiv 2020).

And we already know that the natural hosts of SARS and MERS, both of the coronavirus families, are likely to be bats. Mammals such as bats have high body temperatures and special immune systems, and are natural hosts of many dangerous viruses. From this point of view, the natural host of the new coronavirus is indeed also bats.

Focus on the new coronavirus pneumonia These scientific issues you should be concerned about

But I still have to remind you that, as with identifying a pathogen of an infectious disease, it has always been a very difficult task to identify the natural host of pathogens in nature, requiring us to understand the full chain of viruses from natural hosts to humans. In fact, neither SARS nor MERS viruses have been fully proven.

In fact, more important than confirming a natural host is to identify the intermediate host of the new coronavirus — that is, to find its middle chain from bat to person. You know, although the new coronavirus and Yunnan chrysanthemum manta rays are highly similar to the virus, but the 4% difference actually means that the virus in bats is less likely to directly infect humans. In addition, virus samples in patients with neo-coronavirus pneumonia are highly consistent with each other’s genetic sequences, which in itself suggests that the virus should have started to erupt after evolution in some intermediate host (http://www.chinanews.com/gn/2020/01-26/9070200.shtml).

In the case of SARS and MERS, scientists identified beavers and camels as the most important intermediate hosts of the two viruses (Kan B et al J Virol 2005; Sabir JSM et al Science 2015), which spread and mutated widely within their populations and eventually became straight viruses that invade the human body and cause disease. So in the case of the new corona virus, who is the possible intermediate host? The answer to this question is crucial to us from the resurgence of the new coronavirus in the future.

Focus on the new coronavirus pneumonia These scientific issues you should be concerned about

Unfortunately, we don’t have a good guess at the moment. Because most of the early cases are related to the South China seafood market in Wuhan, there is a mainstream guess that perhaps some kind of wild animal being sold there is the intermediate host of the virus. Unfortunately, scientists didn’t have time to collect wildlife samples before the market was closed, so they only had time to test the market environment and did find the virus (http://www.xinhuanet.com/politics/2020-01/26/c_1125503792.htm). Here I can give a rough guess: this intermediate host should be some kind of semi-wild mammal that can be reared on a largescale scale, so as to provide time for the accumulation of mutations in the virus; In the future, regulating and cracking down on wildlife trafficking will certainly be a very important measure for infectious disease control.

So to sum up, based on what we know so far, it’s probably possible to speculate that the source of the virus might be this:

A coronavirus that is parasitic in bats has, for some reason, entered a semi-wild mammal that is largely bred by humans, where the virus acquires the ability to infect human cells and continue to spread between human individuals through widespread mutual transmission and mutation; It infected a part of Wuhan’s residents and led to a large-scale outbreak of the disease.

Focus on the new coronavirus pneumonia These scientific issues you should be concerned about

By the way, based on these discussions, you can certainly understand that the high probability of this virus is not passed directly from wild bats to humans, and there is virtually no evidence that bats are sold in the South China seafood market, or that Wuhan residents have a particular interest in this food.

Of course, there are still many questions that cannot be answered in this simple speculation. For example, according to the latest research, the first infected person of the new coronavirus pneumonia did not actually have contact experience in the South China seafood market, many of the first few patients have never been to this market (Huang C et Lance alt 2020), then how on earth did they get infected? Is the virus capable of spreading efficiently between people from start to the beginning? Or is the virus another source of infection? These questions still need to be seriously studied and answered.

2. How will the disease develop?

To measure the effects of an infectious disease, a rough idea is to consider two dimensions: toxicity and transmission. The former measures the severity of symptoms if a person develops the disease, while the latter measures how likely a person is to have the disease.

There are some rough estimates of the toxicity of the new coronavirus pneumonia. Of the more than 40 people who were initially hospitalized, the mortality rate was as high as 15 per cent and the proportion in intensive care was more than 30 per cent, which exceeded THE level of SARS (Huang C et al Lancet 2020). But if you take into account more patients with mild symptoms, the combined mortality rate is currently around 3% (you can count itself using updated data), well below the levels of SARS (10%) and MERS (35%). And given that most patients have mild or never medical treatment or viral testing, a reasonable guess might be whether the 3 percent mortality rate or the much overestimated figure.

And for the spread of the virus, there is a relatively simple quantitative indicator, called the basic number of infections (R0), which means that an infected person can be transmitted to several people on average without external intervention. Predictably, the larger R0, the stronger the spread, and if R0 is less than 1, it means that the disease will slowly self-desify. For comparison, data on the spread of several important infectious diseases in human history are listed: measles (12-18), smallpox (3.5-7), influenza (2-4), and SARS (2-5).

There are no good estimates of new coronavirus pneumonia. This is partly because the initial number of cases of the disease is likely to be less accurate, and partly because the number of diagnoses is in rapid change. On January 23rd the World Health Organization gave a rough estimate of between 1.4 and 2.5, meaning it is far less powerful than SARS. https://www.who.int/news-room/detail/23-01-2020-statement-on-the-meeting-of-the-international-health-health-health-(2005–committee-from-the-age-the-outbreak-of-go–go–coronavirus-(2019-ncov). But there are also some studies that suggest that the new coronavirus is more powerful than this, and even models that R0 will be around 4 (Read JM et medRxiv 2020) or even about 5 (Zhao S et al bioRxiv 2020)!

To know that the small differences in R0 values can lead to several or even dozens of times the number of infections, r0 estimates need to be very careful and comprehensive, and this data is one of the core information needed to be mastered by infectious disease prevention and control. In this regard, we still need more data from front-line scientists and doctors!

So I can only give a rough and cautious guess here: the new coronavirus is far less toxic than SARS (but significantly stronger than the flu), and the spread should be less powerful than SARS. Therefore, I am highly optimistic about the solution of this sudden infectious disease.

3. How will the disease eventually be solved?

In the face of a new type of virus-induced infectious diseases, the first reaction is certainly, “there is no special medicine”, “there is no vaccine.” Hope to have good drugs to help us kill the virus, can have a vaccine can help us quickly form immunity, prevent the virus from attack.

Focus on the new coronavirus pneumonia These scientific issues you should be concerned about

There is a lot of good news in the news, such as the Shanghai Institute of Medicine of the Chinese Academy of Sciences and the Shanghai University of Science and Technology scientists have teamed up to find 30 compounds that may be effective against new coronaviruses (http://www.cas.cn/syky/202001/t20200125_4732909.shtml); Vaccines can be developed.” (https://news.163.com/20/0126/18/F3RBL23Q0001899O.html). There’s a lot of news like this, and it’s not listed here anymore.

These efforts by Chinese scientists are certainly commendable, but unfortunately, special drugs and vaccines are hardly the saviours we expect for a new virus and an explosive epidemic.

The truth behind this is not difficult to understand, drug development is good, vaccine development is also good, from the start of research to the real mass production, even if all goes well, it will still take a long time. And the time window for preventing and controlling infectious disease outbreaks is far from that long. At the end of the day, the distant water does n’up to thirst.

Let’s take SARS as an example, a serious respiratory infection that broke out in Guangdong, China, at the end of 2002 and was gradually brought under control in the summer of 2003. But the SARS virus vaccine did not start human trials until the spring of 2004, when SARS was officially completed, and by then SARS had disappeared and there was no need for mass production and vaccination (http://news.ifeng.com/mainland/special/h7n9/content-3/detail_2013_04/13/24174901?0.shtml). Drug development is even more so, so far humans have not really developed a specific drug for SARS, in the actual treatment is still supporting treatment-based. The so-called support ive therapy is to maintain the survival of patients through assisted breathing, anti-infection, rehydration and so on, and then wait for the patient’s own immune system to eliminate the invading virus. In fact, for most virus-induced infectious diseases, humans do not have very good specific drugs to eradicate the disease. Examples include hepatitis caused by hepatitis B virus, influenza caused by influenza virus, MERS and SARS virus-induced respiratory syndrome, etc.).

17 years ago SARS so, in the face of a sudden outbreak of new coronavirus pneumonia, it is unrealistic to expect scientists to come up with special drugs and vaccines overnight, who patted the chest is useless, chest beats are useless.

Of course, compared to SARS 17 years ago, scientists on the new coronavirus pneumonia research and understanding is much faster, much deeper, and the previous research experience on SARS also suggests some possible directions. For example, the above-mentioned Chinese Academy of Sciences Shanghai Institute of Medicine and Shanghai University of Science and Technology joint research suggested that several old drugs against HIV may also be effective against the new coronavirus, in fact, unfortunately in the front line infected with the virus of the first hospital wang Guangfa director, he tried a called “Lopina Veletonavir” AIDS drugs, it seems that it does significantly alleviate the disease. (http://www.chinanews.com/gn/2020/01-23/9068406.shtml) These clues certainly help us find drugs that can aid new coronary pneumonia. What’s more, the rate of vaccine preparation in humans is much higher today than it was 17 years ago, and there are even research institutions that plan to conduct clinical trials of the vaccine within a few months (such as Moderna’s RNA vaccine (https://investors.modernatx.com/news-releases-release-details/moderna-announces-funding-award-cepi-development). RNA vaccines can theoretically have a faster production cycle. But this possibility remains theoretical, and no RNA vaccine has yet been clinically studied in humans.

But in any case, it’s not realistic to say that in the time window where the epidemic is as fast as the fire, it’s really unrealistic to want to complete the development of these drugs and vaccines, clinical validation of the human body, mass production, distribution and use.

But I say this, of course, not that we have nothing to do with the new coronapneumonia. In fact, humans have mastered a very old but unusually effective way to deal with this kind of sudden outbreak of infectious diseases — isolation.

The word isolation is popular, but the medical principlebehind behind it is profound. The core of an infectious disease outbreak lies in its infectious nature: it can be passed directly or indirectly from one person to another or more. If a person with an infectious disease cannot spread to more than one person, the disease will slowly disappear. So even if we don’t have a vaccine that can kill the virus directly, if we can do that – so that people who are already sick can’t continue to spread, so that people who are not sick don’t get infected – then we can effectively prevent and control the disease.

There are three cores of isolation:

One is to find and manage the source of the infection. Scientists have made it clear that the new coronavirus is the pathogen of the outbreak, and that it can spread from person to person, which is why people who are already sick or suspected of being sick are quickly identified and isolated for treatment.

The second is to cut off the transmission channel. As a respiratory virus, the main route of transmission of new coronavirus is through droplets, but at present, people can not completely exclude other routes of transmission (e.g. contact transmission, etc.). Therefore, the most effective way to cut off the route of transmission is to avoid large-scale crowd gathering and long-distance movement.

Third, protect the vulnerable people. In the face of this new virus, it can be said that everyone is susceptible (there have been scientists who have rushed to judge that children are not susceptible people, which is very dangerous and wrong judgment). That is to say, each of us need to do a good job of self-protection, wearing a mask, washing hands frequently, try not to touch the mouth, nose and eyes, reduce travel, and even exercise, etc. , are increasing our own protection.

See here, I believe you can understand the state’s decisive measures to implement medical isolation of patients and close contacts, block traffic, cancel public activities, call on everyone to wear masks to wash their hands frequently.

We can even assume a very extreme situation: if people across the country are isolated behind closed doors for two weeks from today (considering that the maximum incubation period for neo-coronavirus pneumonia is around two weeks), and if symptoms of neo-coronavirus pneumonia are quickly transferred to specialized medical facilities for isolation and treatment, then we can completely eliminate the threat of the virus in two weeks (https://www.yicai.com/news/100481245.html).

Of course, this extreme situation is not really possible to achieve, after all, the whole society still needs orderly operation, a large number of material flow in inevitable, there are a large number of people can not completely stay at home, and the detection of the virus can not be so accurate and efficient. But given that the country has implemented strong control measures in cities such as Wuhan, where the infection is dense, and other provinces and cities are also carefully screened and quarantined the cases exported, I am confident that the spread of the virus can be quickly eliminated. In fact, from 1374 Venice closed the city against the Black Death, to 1910 Woolende cut off the railway to fight the plague in the Northeast, and then to this time Wuhan city around the strict prevention of death against the new coronavirus pneumonia, isolation, has always been one of the most effective measures of human resistance to severe infectious diseases.

4. How are Chinese scientists doing in the fight against infectious diseases?

In short, Chinese scientists have done extremely well in this battle;

Let’s start with a good place.

In early December 2019, the first patient was treated for fever and cough, and in the following month more than 40 patients with similar symptoms were treated, and at the end of December, wuhan Health and Health Commission issued a warning of “unexplained pneumonia”. In a month’s time, scientists and doctors were able to detect a whole new type of respiratory infection, which is already a remarkable speed. Knowing that winter is already a time of high incidence of influenza and other respiratory diseases, it is already a great job to find out exactly how many thousands of people in Wuhan may see for respiratory symptoms every day.

Then Chinese scientists are more efficient: after that, on January 7, 2020, scientists confirmed that the new coronavirus was the pathogen of this unexplained pneumonia (http://www.xinhuanet.com/politics/2020-01/09// c_1125438971.htm), the virus genome sequence was completed on January 10 (Wu F et al BioRxiv 2020), and on January 24th the human-to-human capability of the virus was strictly demonstrated (Chan JFW et lancet 2020). These efforts provide scientific guidance for the government to take strong measures to prevent and control diseases. The efforts of the Chinese scientists we just mentioned to screen drugs and prepare vaccines are indeed very valuable.

From the chaos of SARS in 2003 to the rapid and precise response to the new coronavirus, the progress of Chinese science and Chinese scientists is our common pride.

But I still feel that there are some issues worth discussing, even criticizing:

For example, most of the research we see is published in internationally renowned academic journals, such as the New England Journal of Medicine, The Lancet. This is certainly a high degree of recognition of the quality of these studies, but given the urgency of infectious disease prevention and control work, is it really necessary to publish papers as a top priority to complete the work? Does the process of publishing a paper (writing, reviewing, modifying, etc.) delay the sharing of information? I even noticed that some papers require a paid subscription to get it, which means that other Chinese scientists and disease prevention and control departments are not free to access these research results and move on to the next step! In the face of dangerous and urgent epidemic prevention work, do Chinese scientists have a faster, more reasonable and extensive channels to disclose their research results? I have also noted that many Chinese scientists have chosen free and open platforms such as bioRxiv to upload their research papers, which is undoubtedly commendable. In fact, in the final analysis, the highest state of scientific research, is not to write the results in the human world, written in the land of the motherland?

For example, I have also noticed that within the Chinese scientific community, many “following the wind” “hot spot”-style papers appear. For example, after the virus gene sequence was published, several papers were quickly published. What they have in common is a simple bioinformatics analysis using viral sequences, leading to bold “guesses” such as the possibility that the new coronavirus may be so close to SARS that it may be in the bat, that the intermediate host may be snakes, otters, etc. (Xu X et al, Science China Life, etc. Sciences 2020; Guo Q et bioRxiv 2020; Ji W et J Med Virol 2020). There is nothing wrong with these guesses on academic publication, but there is a clear lack of rigorous data support. We certainly want to guarantee the freedom of exploration and freedom of publication of scientists, but in the early days of the epidemic prevention efforts, the information was extremely confusing and lacking, and any possible misdirection, which I think we need to avoid.

Moreover, although the speed of Chinese scientists in identifying pathogens is staggering, the information on viral genetic sequences published so far is still limited (26 sets of data), which is far from sufficient to reveal the early trajectory of virus outbreaks and to analyze the evolution of viruses in populations. Research and data sharing in this area still need to be strengthened. And we also have to pay attention to, in the research work has been carried out, the various research institutions and research groups can do information and research results can be effectively shared, will not be neighbor-by-side exclusive data, but also we need to be alert in advance.

5. What can Chinese scientists do next?

I think one of the lessons we have to learn is that after SARS subsided, most of the SARS-related research and drug research and development efforts have been halted because of lack of financial support and market prospects. Considering that the path of the new coronavirus to invade the human body is very similar to SARS, imagine that if many studies of that year persisted, today we may have more abundant scientific and medical preparations in the face of the new coronavirus. We may have to reflect on whether the attention of our entire scientific research system to infectious diseases is not enough?

From a broader perspective, the new century, SARS, H5N1 influenza, H7N9 influenza, MERS, the continuous occurrence of the new coronavirus, in fact, is in itself a high warning to human society. Despite our unparalleled human civilization and a highly developed information society, very primitive viral life can still be devastating to the human world.

Focus on the new coronavirus pneumonia These scientific issues you should be concerned about

More importantly, the emergence of these viruses may in itself be a “product” of the high development of human civilization. With more and more of our invading animals and plants in their natural habitats, more and more poultry and livestock to meet our living needs, those naturally inhabited by animals of micro-organisms to gain more and more opportunities to invade the human body. The highly dense community environment in the human world, highly developed network of people and material flow, and provide a hotbed for the epidemic.

Bill Gates once said publicly in a speech that if there is anything that could kill tens of millions of people in the coming decades, the most likely is a highly contagious virus because we have invested so little in the system to prevent the outbreak, and we are not ready to prevent a major outbreak.

And a significant portion of the burden will fall on the shoulders of scientists. To study the origin and evolution of various microorganisms, to study the spread of human infectious diseases and mathematical models, to establish more accurate disease early warning and tracking systems, to develop drugs, to prepare vaccines, and to study the basic biological mechanisms of diseases. All this work is our future mission.