by Sanjay Gupta
The Lab Leak Theory
The “lab leak” theory is one that Jamie Metzl has long believed. He has been maintaining a thrilling diary of facts to make a strong case for the origins of COVID coming from the Wuhan Institute of Virology (WIV).19 Metzl, with whom I worked in the White House during the Clinton administration, wears many hats and is a geopolitical expert on China. With a PhD from Oxford, a JD from Harvard Law School, and as a Phi Beta Kappa graduate of Brown University, his résumé is long and accomplished. He is also a wicked-fast triathlete, a man in a hurry. He has served at the US National Security Council, State Department, Senate Foreign Relations Committee, and as a human rights officer for the United Nations in Cambodia. In 2019, he was appointed to the WHO expert advisory committee on human genome editing. He is also senior fellow for technology and national security at the Atlantic Council, a think tank in the field of international affairs. He knows a thing or two about China and its hand in playing games with viruses. According to him, there’s an 85 percent chance the pandemic started with an accidental leak from the Wuhan Institute of Virology and a 15 percent chance it began in some other way. He was one of the first in Washington, DC, to say the novel coronavirus could be a Wuhan lab escapee, and now he hopes to make the lab leak hypothesis an accepted possibility, not a conspiracy.
Wuhan is a city of 11 million people in central China, making it just the ninth most populated Chinese city. (Shanghai has 26 million people and Beijing 22 million.) Before COVID, you had probably never heard of Wuhan, but it has been on the science community’s radar for some time because it is also home to the country’s first BSL-4 lab (short for biosafety level 4). That is the highest biosafety level, reserved for labs that study the most frightening organisms—ones that are easily transmitted and highly fatal. BSL-4 labs are, for example, where extraterrestrial material would be studied. Laboratory workers don positive pressure suits, and everything they wear and touch is decontaminated (just as you see in the movies). Individuals go through chemical showers when exiting these labs, and if you look around, you won’t find a single sharp edge that could cause an accidental tear in a glove or a gown. It’s the kind of place where you would study organisms that have pandemic potential, such as bat coronaviruses, which is what this particular institute is known for doing. That said, it’s been publicly acknowledged by the lab that prior to the pandemic, a lot of coronavirus research, including some involving live SARS-like viruses, had been conducted in less secure BSL-3 and even BSL-2 laboratories.
To be clear, Metzl is not suggesting the virus was totally genetically engineered or altered deliberately by mad scientists seeking to create bio-weapons. Nor is he dismissing the possibility it was purely born from nature outside the lab in a random leap from a wild animal to a human. But for him, the lab theory must be thoroughly investigated. He believes the bio-weapon that is COVID-19 was born in nature but then possibly bred by science. It received an education to better infect humans. Dr. Bob Redfield, the former head of the CDC under Trump, believes this too. “It’s not unusual for respiratory pathogens that are being worked on in a laboratory to infect the laboratory worker,” Redfield told me. “And can you imagine if that laboratory worker then was asymptomatic? They wouldn’t even know they were infected, right?” The implication is that a single asymptomatic person could be the tip of a pandemic-sized iceberg.
Redfield finds it implausible, if not impossible, that a virus could jump directly from an animal like a bat or civet cat to a human “and immediately become one of the most infectious, transmissible pathogens known to humanity.” He explained to me that it doesn’t make biological sense for a pathogen to go from a wild animal to a human and spontaneously be extraordinarily efficient at human-to-human transmission. It takes a while for pathogens to gain that level of fitness, or function. They sputter along for a while as they gain their athleticism to flex their muscles in human hosts. Like Metzl, Redfield finds it more plausible that the virus was being studied and educated in the lab, interacting with human cells—the training grounds for superb adaptation—before being accidentally unleashed on the public. “Most of us in a lab,” Redfield explained, “when trying to grow a virus, we try to help make it grow better, and better, and better, and better, and better, and better so we can do experiments and figure out about it.” It is often referred to as gain-of-function research—you tweak microorganisms in a lab in either petri dishes or other animals to make them more infectious. You teach it to do certain things. It’s performed with the expectation that the transmission, and possibly the virulence, of the pathogen will be enhanced. Why would you do that? To stay one step ahead of the virus—to one-up mother nature. In nature, viruses don’t want to become too lethal because if they kill their host, they “die” too. They reach a dead end, failing to multiply. Viruses devolve to something weaker, thereby surviving and proliferating. So when a bad virus gains a unique advantage to efficiently infect more and more humans, you have to wonder how it earned its wings.
“That’s the way I put it together,” Redfield concluded. He was clear that he’s merely giving his opinion now that he’s allowed to as a private citizen, but an opinion from the former CDC chief, who had access to raw data and intelligence gathering, is not the opinion of just any private citizen. Even Chinese scientists in Wuhan were raising concerns as early as January 2020, as two from separate universities asked an excellent question: How did a novel bat coronavirus get to a major city in the dead of winter when most bats were hibernating, and turn a market where bats weren’t sold into the epicenter of an outbreak? Their resulting paper, which pointed to two local laboratories where research on bat coronaviruses took place, lived on the Internet for a blip in time before vanishing. We may never know how many papers like that as well as scientists and journalists were disappeared from China.
In January 2021, the WHO led a team of international scientists to Wuhan in search of the pandemic’s origin. But after a full year had passed, much evidence was no longer available and the wet market in question had long been cleaned up and sealed off. It was a highly curated, chaperoned field trip hosted and controlled by the Chinese government, and its conclusions only led to more questions. Did the virus escape from the Wuhan lab where they’d been playing with coronaviruses for a while, and even working on their attachment to the same receptors in human cells as the COVID virus targets? We know this from published papers and research notes.20 The institute has become a world leader on bat coronaviruses and has established one of the largest strain collections, but this lab also has a history of lax safety standards. The world’s outbreak began right in its backyard. Its lab director, Dr. Shi Zhengli, published studies about manipulating bat coronaviruses in a way that could make them more infectious to humans.21 Also known as “Batwoman” for her long history of hunting for coronaviruses in bat caves to study, Zhengli and her colleague Jie Cui are the ones who discovered that the SARS coronavirus likely originated in a population of cave-dwelling horseshoe bats in the Yunnan province in southern China. In their 2017 paper that reported their findings, they warned that “another deadly outbreak of SARS could emerge at any time.”22
In another twist of prophetic irony, Zhengli had published a paper back in 2010 describing a scenario in which infected rodents led to a deadly virus being leaked from a Chinese lab. The paper, titled “Hantavirus Outbreak Associated with Laboratory Rats in Yunnan, China,” reported on an incident in which an outbreak of the deadly hantavirus, which causes fever and kidney failure, occurred at a college in Kunming as the result of a lab leak in 2003.23 In published interviews with Zhengli, she recalls thinking that when a coronavirus was identified as the cause of the pandemic, she wondered herself if it came from her lab.24 To be clear, Zhengli’s goals in studying these viruses and playing with their functionality do not necessarily have malicious intent. It’s how scientists learn more about the virus’s biological mechanisms behind its transmission and replication. It’s also how we can discover possible mutations that ma
y take place and ultimately allow better community surveillance, identifying when such mutations arise and permitting vaccines to be prepared in advance of such an outbreak. But clearly there’s a fine line here that can cloud over.
Metzl has been critical of the 2021 probe, which allowed China to collect its own data and then hand it over to the WHO team, comparing it to tapping the Soviet Union to “do a co-investigation of Chernobyl.”25 He also enjoys quoting Humphrey Bogart from Casablanca: “Of all the gin joints in all the towns in all the world… why Wuhan?” Metzl highlights three facts that barely made the news. Number one: In 2012, six miners working in a bat-infested copper mine in Yunnan province were infected with a bat coronavirus. All of them developed symptoms exactly like COVID. Three of them died. Number two: Viral samples from these miners were taken to the Wuhan Institute, the only level 4 biosecurity lab in China that was also studying bat coronaviruses. And number three: When COVID made its bona fide Wuhan appearance in late 2019, its closest known relative was the same virus sampled from the Yunnan mine where the miners had been infected.
The SARS outbreak nearly twenty years ago should have served as a wake-up call, showing us that coronaviruses can cause fatal respiratory illness and should not be ignored. It also exposed the real possibility of lab leaks. But it didn’t prove to be a good enough villain: It didn’t scare Americans because no one here died from it; only eight people in the United States were determined to have contracted the virus from traveling. It also didn’t transmit easily during its relatively short, two- to seven-day incubation period. So even though scientists comparing the two viruses in recent studies determined that SARS was more lethal than COVID, it was not as contagious. COVID shares 79 percent genome sequence identity with SARS, but it is unique—and wicked—in its ability to infect. Indeed, the son of SARS has proven to be a far more social microbe, and it likes to travel quickly. It also takes its time to trigger symptoms in infected people who go on to develop the disease and show signs of illness. Meanwhile, these people are unknowingly infecting others—perpetuating the chain of transmission.
Big and Sticky
The RNA virus that causes COVID has a relatively large genome. Comprising a string of roughly 30,000 biochemical building blocks (again, these are called nucleotides) enclosed in a membrane of both protein and fat, it’s more than three times as big as HIV and hepatitis C and twice the size of the average flu virus. But it’s still tiny, coming in at barely one-thousandth the width of a human hair. This may be difficult to picture, but as Alan Burdick described it for the New York Times, “If a person were the size of Earth, the virus would be the size of a person.”26
COVID is a savvy RNA virus. Its core code contains genes for as many as twenty-nine proteins, four of which give the virus its structure. The “S” protein, for instance, is of particular importance because it creates the spikes on the surface of the virus and unlocks the door to the target cell. This protein latches onto, or binds, to a receptor called angiotensin converting enzyme 2 (ACE2) on cells to gain entry. The S protein acts like a key inserting itself into a lock. The spike protein on COVID is nearly identical in structure to the one on SARS, but some data suggest that it binds to the target docking station far more snugly. It’s sticky. Some researchers think this may partly explain why the new virus is so efficient at infecting us.27 The other proteins encoded by the RNA serve various roles once the virus has entered a cell through the ACE2 cellular doorway. They hijack the cell’s machinery and effectively turn off the cell’s alarm system, commandeer the copier to make new viral proteins, and help the buds of new viruses shape and prime themselves for bursting out by the thousands to go on the prowl and infect other cells. If mistakes are made during the copying process and mutations occur, voilà—there’s the birth of a new variant. Maybe it’s more lethal or less, but rarely do variants lose their ability to perform their main function: infect, replicate, and spread. And repeat, over and over again. Often the variants that can infect more efficiently, as has been the case for the B.1.1.7. (Alpha) strain from the United Kingdom, become dominant strains; they can “run faster” to new hosts and outrun older strains, pushing them out of business. The Delta strain originally from India has also proven to be crazy fast and infectious.
Mutant strains of COVID will likely keep us hunting down the virus and firing at it with our vaccines, even though coronaviruses change more slowly than most other RNA viruses. That’s probably because of a “proofreading” enzyme that corrects potentially fatal copying mistakes. A typical COVID virus accumulates only two single-letter mutations per month in its genome—a rate of change about half that of influenza and one-quarter that of HIV. Dr. Birx knows this territory well from her experience in the HIV world where variants foil attempts to control the HIV pandemic. “The virus is not thinking,” she explained. It’s not saying, Hey, I should be better at getting into cells, so let’s change the type of key I have so I fit better into the lock. The virus is not proactively developing strategies and tools to infect us better or to escape our immune system and retaliatory attempts with drugs and vaccines. It’s simply morphing under nature’s forces, including the pressures we place on it. It has no plan or endgame other than to multiply. I love how Burdick sums up the real meaning of COVID: “To know [COVID] is to know ourselves in reflection. It is mechanical, unreflecting, consistently on-message—the purest near-living expression of data management to be found on Earth. It is, and does, and is more. There is no ‘I’ in a virus.”28
When you put immune pressure on a virus, whether through treatment or an immune response, induced by either monoclonal antibody infusions or vaccination, the virus randomly mutates. And if it finds a mutation that helps it multiply better, then that virus becomes the predominant virus. Birx has seen this with HIV in communities of spread, watching HIV change its wardrobe.
This phenomenon is the basis for molecular epidemiology, a study aimed at understanding and mapping the mutations in the virus’s genetic sequence that give rise to the variants gaining dominance. I should point out that one of the key differences between HIV and COVID is that HIV never clears the body; it hides from the immune system, concealing itself in lymphocytes, or white blood cells, that are intrinsically hard to kill because they are resistant to killer T cells. Hence, HIV-positive patients remain positive because they are never cured. It remains a mystery why the body does not make an adequate immune response to HIV. COVID, however, apparently persists until the body’s immune system can deactivate the virus and clear it away, rendering a person negative if he or she can survive the effects of the infection.
Unlike the first SARS (sometimes called SARS Classic), which quickly finds a nice home in our lung cells with symptoms soon to follow, the son of SARS prefers to colonize quietly in the nose and throat before moving into the lungs. During this first phase of infection in the first week or so, a person may have mild cold-like symptoms (called paucisymptomatic) or no symptoms at (called asymptomatic) but still be highly infectious, shedding copious amounts of virus. The individual may develop a fever, dry cough, sore throat, loss of smell and taste, or head and body aches. Once the virus reaches the lungs, it’s a whole new landscape as the infection enters a second phase. The delicate alveoli there—tiny sacs lined by a single layer of cells rich in ACE2 receptors—become compromised. The alveoli are responsible for trafficking the exchange of oxygen and carbon dioxide, so any compromise to them is a compromise to the whole body. The cascade of events that turns the lungs into a swampy mess can lead to pneumonia. For some, the infection steals so much of their breathing capabilities that they experience acute respiratory distress and need oxygen, sometimes a ventilator. Autopsies on COVID victims put on ventilators have shown that their alveoli became stuffed with fluid, white blood cells, mucus, and the detritus of destroyed lung cells.
The damage that COVID inflicts doesn’t end with the lungs or respiratory system. In fact, no system in the body seems to be spared from potential insult, leading many scient
ists studying COVID’s far-reaching effects to characterize it as a vascular disease. And those ACE2 cellular doorways are scattered prominently throughout the body in many cell types and tissues, including the lungs, heart, blood vessels, kidneys, bladder, brain, eye, pancreas, liver, and gastrointestinal tract. Because they are present in epithelial cells, which line certain tissues and create protective barriers, there is probably no organ or system in the body free of this critical receptor. It’s even found in the prostate and testes, as well as the placenta. The ACE2 system is crucial to many biological processes, notably things like blood pressure regulation, wound healing, and inflammation. When the virus binds to and essentially clutters those ACE2 receptors, it prevents ACE2 from performing even the most basic critical functions.
The ubiquity of the ACE2 receptors partly explains how COVID can be so insidious far beyond the lungs and result in a perplexing array of conditions from head to toe. In addition to making the lungs ground zero (and a functional launch pad for spewing more viral particles to infect others), it can attack the lining of blood vessels and generate clots; harm the muscular walls of the heart; generate strokes, seizures, and inflammation of the brain; and hurt the kidneys. And one of the virus’s greatest strengths appears to be its after-effects—the debris it leaves after the immune system has neutralized the virus. The actual virus may be gone, but it’s not forgotten as the body remains stuck in a pro-inflammatory state. Future research will figure out why one person who contracts the virus experiences no symptoms while someone else is dead within days. Or why someone with a mild case goes on to have a long bout with a multifaced, prismatic illness. Or, most mysterious, how young children can develop chronic symptoms of illness months after an infection they never knew they had. The answers are probably not monochromatic. A complex constellation of factors—from purely genetic to environmental and the presence of preexisting conditions—is likely at play when it comes to explaining the vast spectrum of illness we’ve seen across individuals stricken with COVID. In fact, some studies are underway to determine if genetic differences in people result in how their ACE2 receptors function, putting one more or less at risk for a bad outcome from a COVID infection.29 Variations of the ACE2 receptor could be a function of age, gender, and even ethnicity.
