King Virus
The coronavirus is responsible for a third of all head colds, but the recent
outbreak of SARS has put this relatively unknown virus on the royal road to
infamy.
The virus that causes severe acute respiratory syndrome—known by its acronym, SARS—is about a tenth of a micron (1/25,000 of an inch) in size. But in the world of viruses, it is king. For one thing, it carries within its protein coat the largest known viral RNA genome—31,000 nucleotides long, as compared to less than 10,000 nucleotides in HIV, for instance. And it wears a crown made of protein spikes.
Still, when SARS first spread its way into the limelight in November 2002, the coronavirus was a relative unknown. After all, no one had ever linked a human coronavirus to anything more disruptive than the common cold. (Coronaviruses are behind about a third of all head colds.) Nonetheless, soon after the epidemic began, scientists began pointing their fingers its way, speculating that somehow this benign bug had turned into a killer.
And once the name coronavirus began to be bandied about, the eyes of the world turned to Keck School of Medicine of USC and Michael M.C. Lai, M.D., Ph.D., Distinguished Professor of Molecular Microbiology and Immunology and Neurology, a Hastings Foundation Professor and a Howard Hughes Medical Institute Investigator.
Dubbed “the father of the coronavirus” by his hometown paper, The Taipei Times, Lai seems both bemused and energized by the attention this obscure family of pathogens has garnered. “I have been studying coronavirus for nearly 30 years,” he says, “and have not anticipated that this virus would ever attract this much attention.”
Ascent to the throne
Although SARS had been infecting people in the Chinese province of Guangdong for months, public and scientific recognition of the epidemic began in February 2003, when a Chinese-American businessman arrived in Vietnam after a visit to Hong Kong. The man became very ill very quickly, recalls Fred Sattler, M.D., an infectious disease specialist and professor of medicine at the Keck School. “A Vietnamese epidemiologist saw the case and became suspicious that something was wrong when a number of health care workers became ill shortly thereafter,” Sattler recounted at a recent symposium on the disease held at the Keck School. That epidemiologist alerted the local health authorities, who alerted the World Health Organization (WHO), which sent a team to investigate. And the panic began.
SARS’s worldwide impact was almost unprecedented. Severe acute respiratory syndrome went from literal oblivion to household acronym in just a matter of weeks. It resulted in travel advisories being issued for all or parts of China, Taiwan, Hong Kong, Vietnam and Singapore, as well as a travel “alert” for Toronto, Canada, all of which further devastated an already-reeling travel industry. It even affected medical research, forcing the cancellation of meetings scheduled to take place in cities considered hot spots for the disease.
In its early stages, SARS mimics influenza—the flu. Fever, dry cough and shortness of breath come first. Then comes the pneumonia—a pneumonia so severe that it can be lethal even to young, previously healthy adults, the kind who usually shrug off the flu in a couple of days.
By the time the epidemic had officially ended—the WHO stopped its daily updates of numbers of cases on July 14, and later defined the outbreak as having stretched from Nov. 1, 2002 to July 5, 2003—there were 8,437 probable cases of SARS worldwide, with 813 deaths. In the United States, there were just 75 probable cases, with one death.
These statistics are dwarfed by those attached to any number of other infectious diseases, notes Sattler. In the United States alone, somewhere between one in four and one in five people come down with the flu each year, according to the Centers for Disease Control and Prevention. The exact numbers are difficult to track because it is not a “reportable” disease. In addition, notes Sattler, “Each year more than 35,000 people in the United States die of influenza and 114,000 need to be hospitalized.”
So what made SARS—and, by association, the coronavirus—so fascinating and terrifying to so many people? Undoubtedly, the mystery surrounding the disease gave it much of its allure. Take, for instance, the spread of SARS. Researchers are still not sure how SARS is spread. The assumption is that it travels by way of droplets expelled by infected patients when they cough or sneeze, much as colds and the flu are spread. And during the early days of the epidemic, even that was in question.
Without a known mode of transmission, containing the spread of the disease became a race against the clock. Physicians and health researchers were forced to become medical detectives, tracking down every case and following its chain of transmission. They then used isolation—in Hong Kong, for instance, an apartment building was quarantined for 10 days after 107 people there came down with SARS—until patients were found free of the disease or were no longer considered infectious.
Yet, Lai admits, researchers still do not know if patients, once infected, can be permanently cured or if they might relapse. They do not know exactly how contagious it is during incubation and recovery, or whether there are—as suspected—“superspreaders” of the disease, who cause clusters of infection. For the many questions about SARS, time will be the ultimate judge.
The coronation
When the virus appeared, answering any question was nearly impossible, notes Lai, until scientists knew what was causing SARS. That discovery, thankfully, happened relatively quickly. “It is amazing that within one month, scientists isolated and identified the coronavirus associated with SARS,” says Lai. They did it by growing the SARS-causing virus in specialized cells; when they examined those cells, they found coronavirus-like particles in them. Lai calls this feat “a very lucky break.”
If anyone knows how challenging—and rewarding—the study of the coronavirus can be, it is Lai. Over the years, he has devoted much time and energy to peering into the inner workings of the coronavirus family, examining the ways in which these viral invaders enter their target cells, and how they co-opt those cells’ RNA-making machinery to churn out new copies of themselves. In fact, more than a dozen years ago, Lai completed the genetic map of a coronavirus, sequencing a version found in mice.
While the coronavirus has previously been considered benign in humans, it can have serious neurological consequences in mice and other animals. In fact, coronavirus infection in the mouse makes for a good animal model of multiple sclerosis. Lai—working with Keck School colleagues such as Leslie Weiner, M.D., the Richard Angus Grant Sr. Chair in Neurology, and Stephen Stohlman, Ph.D., professor of neurology and molecular microbiology and immunology—has been using molecular biology approaches to determine which of the genes are behind the virus’s effects in the brain.
The coronavirus has always fascinated Lai, he explains, in part because its 31,000 nucleotides makes it an improbable and unwieldy infectious agent. “Conventional wisdom would say that having such a large RNA genome wouldn’t work, that the virus would become defective,” notes Lai. “But coronavirus seems to have broken all the rules.”
Indeed, Lai and his Keck School colleagues have shown that this viral scofflaw has devised entirely new mechanisms to make copies of its gigantic genome. And he has been working to identify and characterize the proteins used in this process.
Still, it wasn’t until the advent of SARS that Lai’s work in the coronavirus field came into the spotlight. His expertise with the coronavirus made him indispensable to physicians and scientists studying the emerging epidemic, as well as to journalists trying to sort out what was going on. He gave innumerable lectures on coronavirus biology. In May 2002, he returned “home” to Taiwan, where he worked to investigate the spread of the disease and assisted a SARS research team from Academia Sinica—Taiwan’s most prominent academic institution—in its efforts to develop vaccines to prevent the disease and treatments for those already infected.
Lai’s contributions to the team were so valuable that, on July 1, he assumed the post of vice president of Academia Sinica, where he will supervise the institute’s genome and life sciences research. He will retain his position at the Keck School during his time in Taiwan.
The future of the monarchy
Lai says he is exhilarated by all the interest in this field, and excited to be working in the midst of it. Still, he notes, there is much to be learned about the coronavirus that causes SARS—most importantly, where it came from and how it can be controlled.
According to Lai, the SARS coronavirus contains some genes identical to those found in mouse versions of the pathogen, and other genes identical to those found in bird coronaviruses. “My analysis suggests that it likely existed in a wild animal, probably a bird or a rodent,” Lai said in an interview with Popular Science. “It jumped species only recently, when it came into contact with a human being.”
That sort of species-to-species jump is not the coronavirus’s usual modus operandi, and it was likely not an easy one to make. It would have required the acquisition or mutation of genes that would produce whatever the virus needed to allow it to gain entry into human cells.
On the other hand, the sort of genetic and molecular changes that it would have required are not at all out of character for the coronavirus, says Lai. This viral family is known for being extremely changeable. Not only does its own RNA mutate easily, but it is also at ease in picking up pieces of other viruses, such as influenza.
That is why, over the years, coronaviruses have been found in everything from mice and birds to cats, dogs, cows, turkeys, chickens, pigs and humans. “Something like 70 to 80 percent of people have antibodies for a coronavirus,” Lai notes.
So, what next? Lai is upbeat about the prospects for a vaccine. In fact, one of his goals at Academia Sinica will be to organize a research team to actively pursue a SARS coronavirus vaccine. And they will have at their disposal a number of already-successful vaccines against numerous types of coronaviruses in animals. “I expect an investigational vaccine within months,” Lai states.
In addition, scientists at a variety of institutions have already identified regions of the viral genome as targets for drugs, and are sifting through some 20,000 known compounds to determine if any of them will be able to vanquish this particular variety of virus.
Lai and his colleagues are by no means taking the vanquishing of the coronavirus as a given. “Viruses are very intelligent. They can think. They do things that we do not expect. They adapt to the environment. They change themselves in order to survive,” says Lai. “It’s a very dynamic process—that’s why I always feel that viruses are smarter than virologists.
Eye on Epidemics
Severe acute respiratory syndrome (SARS) is certainly not the first communicable disease to be the focus of media attention—think HIV, hantavirus, West Nile—and it already is not the last. As the SARS epidemic began to wane, focus shifted to monkeypox, a rare viral disease that is generally found in the rainforest regions of central and west Africa. When it began showing up in the U.S., right on the heels of the SARS epidemic, it wreaked all sorts of havoc. According to the U.S. Centers for Disease Control and Prevention, most of the 72 suspected cases of monkeypox in this country—spread over just six states—were the result of contact with infected prairie dogs being kept as pets, or by household contact with people who were infected by the prairie dogs.
SARS and monkeypox are also not the only diseases being carefully watched by national and international health-care agencies. The World Health Organization’s Communicable Disease Surveillance & Response (CSR) team keeps an eye on epidemics and newly emerging infections around the globe.
In addition to SARS, the CSR is currently monitoring a number of other diseases, including:
anthrax
lbovine spongiform encephalopathy (mad-cow disease)
cholera and epidemic-prone diarrheal diseases
Crimean-Congo hemorrhagic fever
Dengue/Dengue hemorrhagic fever
Ebola hemorrhagic fever
hepatitis
influenza
Lassa fever
meningococcal disease
plague
Rift Valley fever
smallpox
yellow fever
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