Wednesday, August 12, 2020

COVID-19 in the Evolutionary History of Infectious Diseases (2): The Accidental Animal Origins of SARS-CoV-2

At about 7 p.m. on the evening of December 30, 2019, some samples from hospital patients in Wuhan, China, arrived at the Wuhan Institute of Virology.  The Wuhan Center for Disease Control and Prevention wanted Shi Zhengli's laboratory to decide whether there was a novel coronavirus in two hospital patients with an unusual form of pneumonia.  Shi Zhengli was at a conference in Shanghai.  The director of the Institute called her by telephone to tell her that she should return to Wuhan immediately (Qui 2020).

Shi was worried because this new coronavirus seemed to belong to the same family of viruses as the one that caused severe acute respiratory syndrome (SARS), which had infected over 8,000 people and killed almost 800 in 2002 and 2003.  In 2005, Shi had shown that the SARS coronavirus had probably originated in horseshoe bats in the southern, subtropical Chinese provinces of Guangdong, Guangxi, and Yunnan, and the viruses had jumped from bats to humans, perhaps passing through an intermediate animal such as civets (a mongoose-like animal) (Li et al. 2005).  In 2017, Shi and her colleagues reported that after five years of surveillance of one horseshoe bat cave (Shiton Cave) in Yunnan province, they had found three new SARS-like coronaviruses that were capable of infecting human cells.  She warned that this showed the need for the world to be prepared for the future emergence of new SARS-like diseases (Hu et al. 2017).  Horseshoe bats are found mostly in tropical or subtropical areas, such as the southern provinces of China--Guangdong, Guangxi, and Yunnan.  Consequently, Shi had never expected to find a new SARS-like coronavirus in central China, such as the Hubei province of Wuhan.  So, as she was travelling back to her lab in Wuhan, she thought to herself, "Could they have come from our lab?"  In fact, some people--including Donald Trump--have said that the new coronavirus that has caused COVID-19 escaped accidentally from her lab.  But Shi has denied this.

                                                    Provinces of China.  Wuhan is in Hubei Province.

        A Horseshoe Bat Found in the Southern Provinces of China (Yunnan, Guangxi, and Guangdong)

Most of the newly emerging infectious diseases are zoonotic (originating in animals).  And of these over 70% have their origin in wildlife.  For that reason, some scientists have warned that we are not doing enough to support wildlife disease surveillance like that done by Shi and her colleagues (Morens et al. 2020; Watsa 2020).

The three influenza pandemics of the 20th century--the Spanish flu of 1918, the Asian flu of 1957, and the Hong Kong flu of 1968--were all caused by viruses that originated in wild waterfowl.  The Spanish flu virus--H1N1--killed as many as 50 million people, which made it the deadliest pandemic in human history as measured by number of deaths.  (I have written previously about the Spanish flu pandemic.)  The Asian flu virus--H2N2--killed as many as 1 million people.  The Hong Kong flu virus--H3N2--killed at least 1 million.  All three viruses are strains of the genus influenza virus A.

If these pandemics were to occur today with a global population of 7.8 billion, the equivalent number of deaths would be 218 million for the Spanish flu, 3 million for the Asian flu, and over 2 million for the Hong Kong flu.  By comparison, the COVID-19 pandemic has killed 741,000 people globally (167,000 in the U.S.) as of today (August 12), which indicates that it is likely to be less deadly than these flu pandemics, certainly much less deadly than the Spanish flu.

The SARS outbreak in 2002 was the first emergence of a deadly coronavirus with pandemic potential.  Previously, coronaviruses were known mostly for causing common colds.  At first, scientists thought that the SARS coronavirus had jumped from Asian palm civets to humans.  But later Shi and her colleagues showed that the civet was actually an intermediary animal: the virus had passed from bats to civets and then to humans (Li et al. 2005).

                                                                     An Asian Palm Civet

Shi and others have identified and isolated SARS-like viruses in bats that closely resemble in their genetic sequencing the SARS viruses that have infected human beings.  But none of these coronaviruses in bats perfectly matches the human strains.  What this probably means is that the SARS-like viruses in bats and those infecting humans are evolutionary descendants of some ancestral viruses that split off from the bat virus some years ago.  Bats are good reservoirs for this evolution because they carry many different strains of the virus, and through recombination gene segments can be transferred and mixed between viruses, which provides a mechanism for rapidly generating variants that might happen to have the traits that allow them to infect human hosts.  This is likely what happened in the evolution of SARS-CoV-2, the coronavirus that has caused the COVID-19 pandemic (Letko et al. 2020).  I have written previously about the evolution of SARS-CoV-2.

In less than two weeks after the patient samples had arrived at her lab in Wuhan, Shi and her colleagues had sequenced the genome of what would later be named SARS-CoV-2.  She published the sequencing through the World Health Organization on January 12, 2020.  

By January 22, the coronavirus had spread to major cities and provinces in China, with 521 confirmed cases and 17 deaths reported.  Confirmed cases were also reported in other countries, including Taiwan, Japan, South Korea, and the United States.  

On January 23, the Chinese government ordered the lockdown of Wuhan--a sprawling city of 11 million people--and other cities in Hubei province in an attempt to quarantine the center of the coronavirus outbreak.  The lockdown was officially ended on April 8.  Although quarantining has a long history, this was the first time in history that a government had ordered the shutdown of such a large region and such a large population.  This Chinese lockdown set a pattern followed later by other governments around the world.  By March 28, 2.6 billion people--about one third of the world's population--were under some form of lockdown.  This caused a worldwide economic depression.

The human costs of the COVID-19 pandemic--the deaths from the virus, the social costs of the global depression, and the loss of liberty for people under lockdowns--have provoked people into a search for someone to blame.  And attention has focused on Shi Zhengli's lab in Wuhan.  First, it was charged that the Chinese had used Shi's lab to genetically engineer the SARS-CoV-2 virus as a bioweapon.  But studies of the DNA genome of the virus could not find any of the signs of the standard tools of genetic engineering.  Then some people speculated that Shi--now called the "bat woman"--had found the SARS-CoV-2 virus in a bat, brought it back to her lab, and there someone accidentally became infected with it and carried it out of the lab.

President Donald Trump has said that he has secret intelligence proving that the virus leaked out of Shi's lab.  In a recent interview with Science, Shi has denied this and demanded an apology from Trump (Cohen 2020).  For months after the beginning of the outbreak, Shi was "missing" in China.  But in recent weeks, she has been giving interviews to reporters.  A few days ago, reporters for NBC News were permitted to tour the Wuhan Institute of Virology and interview scientists.  The U.S. State Department has issued a statement saying that NBC News is being used by the Chinese government to propagate China's propaganda to cover up the role of the Wuhan lab in the coronavirus outbreak.

                                                                              Shi Zenghli

Originally, it was thought that since many of the people in Wuhan who first became infected with the virus had been to the Huanan Seafood Market in Wuhan, this must have been the place where the spillover from bats to humans (through some intermediary animal) first occurred.  In China, there is a cultural tradition favoring the eating of exotic wild animals.  At the seafood market, live wild animals were sold for consumption.  So this could have been the point of viral transmission. 

One of the wild animals sold in such markets is the pangolin.  Pangolins look like scaly anteaters.  They are considered a delicacy in China, and pangolin scales are used in traditional medicine.  A coronavirus found in pangolins is very similar in its genome to SARS-CoV-2, which suggests the possibility that it could be the intermediary animal between bats and humans.

                                                                       The Pangolin

The Huanan Seafood Market was closed on January 1.  On February 24, the Chinese government banned all wildlife consumption and "wet markets."  Nevertheless, such bans will not stop the illegal trade in wild animals as long as there is a popular demand for them.

Shi has said, however, that many of the early infected patients had no association with the seafood market.  Moreover, her lab's study of the market could not find any SARS-CoV-2 nucleic acids in frozen animal samples.  She has concluded that the spillover did not occur in Wuhan or in Hubei Province.  It must have occurred in one of the southern provinces, and then some infected people brought it to Wuhan.

According to Shi, in her interview for Science (Cohen 2020), no one in her lab had ever seen SARS-CoV-2 until they received the clinical samples on December 30, 2019.  After they had completed the genetic sequencing of SARS-CoV-2, they saw that it had 80% sequence identity to the three bat coronaviruses that they had isolated over the last 15 years.  They did not isolate the SARS-CoV-2 virus until January of 2020.  An isolated virus is a live virus that can grow in cultured cells in the laboratory.

On February 3, they published a paper reporting that SARS-CoV-2 was 96.2% identical at the whole-genome level to a bat coronavirus named RaTG13, which they had found in a bat fecal sample collected in Yunnan province (Zhou et al. 2020)  But they had never isolated this bat coronavirus.  They had reported in publications (in 2013, 2016, and 2017) the three isolated strains of live SARS-related bat coronavirus.  If they had isolated SARS-CoV-2 before 2020, Shi suggests, they surely would have published this result, and so the lack of such publication should be evidence that they had not isolated it before 2020; and therefore it was not possible for anyone in the lab to be infected by it in 2019.

Shi explains that her lab had not paid much attention to the RaTG13 bat coronavirus prior to 2020 because it showed a low similarity to SARS-CoV, and they had not yet seen SARS-CoV-2.

Shi's study of the viruses carried by wild animals has been carried out in collaboration with Peter Daszak of the EcoHealth Alliance in New York.  They argue that such wildlife virus surveillance is the only way to work towards understanding, preventing, and controlling outbreaks of infectious viral diseases that originate in wild animals.  In April, however, the Trump Administration ordered the termination of their research funding from the National Institutes of Health.  Shi and Daszak have complained that this makes no sense, because their collaborative research is the only way to learn how to prevent future outbreaks.  They estimate that there are more than 5,000 coronavirus strains in bats waiting to be discovered.  "Bat-borne coronaviruses will cause more outbreaks," Shi says.  "We must find them before they find us."

But is it realistic to expect that we will ever be able to find these deadly viruses before they find us?  If the evolution of new viral pathogens from bats and other animals is as accidental, as random, as it appears to be, does that make it unlikely that scientists like Shi and Daszak will ever discover the next SARS-CoV-2 before it can spread among human beings?

After 15 years of research, studying hundreds of viruses found in bat caves, Shi and her colleagues still cannot trace the exact evolutionary history of the SARS-CoV virus that caused the SARS pandemic in 2002.  So, can't we expect they will have the same trouble in tracing the history of the SARS-CoV-2 virus causing the COVID-19 pandemic?

Or could their research at least teach us how to lower the likelihood of viral spillovers from animals to humans--perhaps, for example, by shutting down the markets for live wildlife?


Cohen, Jon. 2020. "Wuhan Coronavirus Hunter Shi Zhengli Speaks Out." Science 369: 487-488.

Hu, Ben, et al. 2017. "Discovery of a Rich Gene Pool of Bat SARS-Related Coronaviruses Provides New Insights into the Origin of SARS Coronavirus." PLoS Pathogens 13 (11): E1006698.

Letko, Michael, et al. 2020. "Bat-Borne Virus Diversity, Spillover, and Emergence." Nature Reviews Microbiology 18 (August): 461-471.

Li, Wendong, et al. 2005. "Bats Are Natural Reservoirs of SARS-Like Coronaviruses." Science 310 (October 28): 676-679.

Morens, David M., et al. 2020. "Escaping Pandora's Box--Another Novel Coronavirus." The New England Journal of Medicine 382:1253-1254.

Qui, Jane. 2020. "How China's 'Bat Woman' Hunted Down Viruses from SARS to the New Coronavirus." Scientific American (June).

Watsa, Mrinalini. 2020. "Rigorous Wildlife Disease Susrvellance." Science 369 (July 10): 145-47.

Zhou, Peng. 2020. "A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat Origin." Nature 579 (March 12): 270-273.

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