This article on the science of novel coronavirus is part of the Science in Sci-fi, Fact in Fantasy blog series. Each week, we tackle one of the scientific or technological concepts pervasive in sci-fi (space travel, genetic engineering, artificial intelligence, etc.) with input from an expert. Please join the mailing list to be notified every time new content is posted.
Scientist Roundtable on Novel Coronavirus 2019
SARS-COV-2, the novel coronavirus associated with the COVID-19 outbreak, is the subject of worldwide media attention and curiosity. It’s more important than ever for the general public to get factual information from trusted, well-informed experts. Thus, I’ve assembled a panel of expert Science in Sci-fi contributors to answer some key questions about the virus behind the current pandemic.
Jenny Ballif (@JennyBallif) has a background in molecular biology and runs the educational YouTube channel Science Mom, which is streaming a free math and science show during the school cancellation time.
Lee A. Everett (@LeeA_Everett) is a fantasy and science fiction writer who, in her other life, has advanced degrees and professional training in the fascinating intersection between biomedical research and veterinary medicine.
Mike Hays (@coachhays64) is a molecular microbiologist at Kansas State University’s College of Veterinary Medicine who studies how pathogens modulate the host immune system responses to their advantage and ways to exploit those factors to fight inflammatory diseases.
Dan Koboldt (@DanKoboldt) is a genetics researcher and assistant professor of pediatrics who studies the genomic basis of human disease at a major children’s hospital.
Q1: What do we know about the novel coronavirus that might not be common knowledge?
MH: Human coronavirus was historically considered a minor human infectious agent that caused around one-third of all common colds. That all changed in the early 2000s when SARS exploded onto the scene in Asia. In the veterinary medicine field, however, coronaviruses diseases are common pathogens. Canine, feline, bovine, avian, and porcine coronavirus are established infectious pathogens in the veterinary field with emerging agents, such as enteropathogenic porcine epidemic diarrhea virus (PEDV), always a threat.
Both SARS viruses (2004 & 2019) are believed to have “jumped” from natural animal reservoirs to humans through contact. RNA viruses, especially single-strand RNA viruses like COVID-19, are prone to a high mutation rate due to the nature of their replication. A high mutation rate can change a virus’s biological characteristics. Novel viruses usually have some molecular or environmental change that causes them to become more pathogenic or simply to jump species.
Never forget a microbe is driven to survive and replicate. As Michael Crichton said in Jurassic Park, “Life will find a way.”
JB: One reason why bats are such a common source a viruses is because the mechanical stress of flying causes their own DNA to leak into the cytoplasm and their immune systems have developed a response with less inflammation, and as a result, a much higher tolerance for viruses.
DK: It’s widely known that the current coronavirus (SARS-COV-2) and its related predecessor made the jump to humans from animals, probably bats for the fascinating reason Jenny mentioned. What might surprise people to learn is that this process (called zoonosis) is actually the major source of pathogens that infect humans. A comprehensive study in 2001 examined 1,415 infectious organisms — comprising viruses, bacteria, fungi, prions, and other pathogens — and found that 868 (61%) are zoonotic, meaning they can be transmitted between animals and humans.
Q2: What makes it different from other viruses that cause respiratory disease in humans?
MH: One of the biggest differences is the ability of the COVID-19 virus to be transmitted by asymptomatic (mild or no apparent symptoms) carriers. As testing is expanded and more data is collected, the numbers of infected people worldwide may be staggering.
How does the virus do what it does? The outside of the virus is covered with protein structures called spikes. When the spike binds to the host ace2 cell surface protein, it “bends” a neighboring cell surface protein, tmprss2 protease, toward the spike. The tmprss2 cleaves the spike and exposes a fusion protein. The fusion protein integrates into the cell membrane and the virus enters the cell. Inside the host cell, it replicates by hijacking the cell’s machinery to produce copies of its RNA genome, its structural proteins, and assembles new viral particles in the cell’s Golgi complex. Anywhere from 100-1000 complete virus particles are made while the extra RNA genome copies are left inside the cell. These “leftover” genetic pieces are what the RT-PCR screening tests target for detection.
DK: The obvious answer is that it’s a newly emerging pathogen in humans, whereas most of the viruses associated with respiratory disease (e.g. influenza and adenovirus) have been around a while. It’s also a bit surprising that elderly persons are so disproportionately affected. As Mike said, there’s something unusual about the transmission patterns as well.
Q3: There have been other pandemics in (recent) human history. How does this compare?
JB: From the location where we have the most data on testing (South Korea) it would appear that this pandemic is less lethal than the 1918 flu (That’s not necessarily a huge comfort, I realize, but it’s much better than 3.4%).
MH: When scientists evaluate infectious disease risk, they look at several factors like mode of transmission, infectivity, morbidity and mortality, and molecular factors. How does it spread? How good is it at spreading to individuals? What are the symptoms and characteristics of infected patients? How many infected patients die and what are the characteristics of those patients?
One of the numbers many infectious disease experts keep an eye on is the Ro (R naught) value. The Ro value is essentially how many other individuals one individual infects during an outbreak or event. The 1918 Influenza pandemic had a Ro value of ~2.5. The 2014 Ebola outbreak had a Ro ~2. SARS in 2004 had a Ro ~3. The current COVID-19 outbreak has a Ro in the range of 1.4-3.9. One group recently reported in The Lancet the COVID-19 Ro value in Wuhan, China declined from 2.35 the week before travel restrictions were implemented to 1.05 the week after. (Good evidence to support the importance of social distancing and travel restrictions!)
In the end, the COVID-19 pandemic may become one of the most widespread infection events in human history. Hopefully, it won’t also be one of the deadliest. Time will tell.
Q4: What don’t we know about the novel coronavirus that we need to?
MH: The public health community has done a good job of informing the public that although COVID-19 is a respiratory virus like influenza, it is different from the flu. One thing we need to be aware of is there may be two or more strains of the virus circulating. Since RNA viruses are notorious for high mutation rates, these mutations can result in shifts in the viral structural proteins or in the molecular machinery which can change the behavior and elude vaccines or antiviral drugs. They can also make the virus more or less virulent or change the host range. These different strains may also be responsible for the variability in the severity of the disease. The scientific community has done a great job of sharing genomic sequence data from virus isolates in almost real-time response.
DK: We need to know who’s been infected, regardless of whether or not they’re symptomatic. The data we have so far, particularly in the US, are biased in a number of ways. The rapid approvals of testing at commercial, hospital, and academic laboratories this week (3rd week of March, 2020) has increased testing capacity exponentially. I think we’ll find that many more people are positive than previously thought, especially among asymptomatic or mildly-affected individuals. A more complete and less biased picture of infected individuals will inform so many other aspects of SARS-COV-2, especially the etiology of disease and the epidemiology of the pandemic.
Q5: What’s your take on why COVID-19 seems more dangerous to elderly people?
MH: Data from China suggests high blood pressure, diabetes, and heart disease factor in death from COVID-19 infection. Those three factors are more prevalent in elderly populations and coupled with suppressed immune function, may play a factor. Interestingly, that ace2 protein the COVID-19 spike binds to is associated with controlling blood pressure. With this association of ace2 and blood pressure regulation, perhaps there is a more specific relationship that exists there. Definitely worthy of more study.
LE: It’s early to say, but I think COVID-19 is affecting the elderly because elderly people are generally considered “immunocompromised”–their immune systems do not behave as robustly as that of a younger person. They also tend to have co-morbidities, other conditions that may weaken their body’s ability to fight off infection. Co-morbidities may include medical conditions such as heart disease, cancer, and lung disease, but can also include activities such as smoking. Sometimes the co-morbidity itself (ex: lung disease, smoking) might make them more vulnerable to a respiratory pathogen like SARS-COV-2, but sometimes they may be on a drug that suppresses their immune system (like steroids, or drugs that treat auto-immune diseases or cancer). Related to this, they also tend to more frequently visit doctor’s offices, which puts them in closer contact with those who may be ill.
Additionally, SARS-COV-2 is very contagious. So younger, non-immunocompromised people may be carrying the disease asymptomatically (unknowingly) and pass it to the elderly during day-to-day contact. This could include family members, service workers, and caretakers. If you then have a situation where there are many people in a vulnerable population (the elderly) living in close quarters together (assisted living facilities), the disease can spread quickly.
Q6: Realistically, how long will it be until we have a vaccine?
LE: Perhaps mere months for a tested vaccine candidate, but much longer for an FDA-approved vaccine. For the vaccine hunt, investigators are currently examining known vaccine “backbones”, onto which they can attempt to plug various aspects of the coronavirus genome. Once they have a likely candidate, a next step in the process involves evaluating the vaccine in several rounds of in vivo (in life) evaluation. This in vivo evaluation takes place in animal models, and includes toxicity testing, vaccine efficacy, and looking for potential side effects. If the vaccine candidate is successful in the rodent (usually mice*), it will be tested in a larger animal such as a ferret, before moving into a non-human primate model. These vaccine trials are approved by an Institutional Animal Care and Use Committee (ethics committee) and conducted under Good Laboratory Practices, which are highly regulated and extremely well-documented. They are subjected to both in-house audits and quality control checks, and auditing by the drug sponsor. Then the company who created the drug takes all this data and submits an application for approval by the FDA. The FDA will further audit and evaluate the study and determine whether to approve the drug.
Sometimes drugs are used on a conditional basis without FDA licensing, in people who have a high likelihood of exposure. Some examples include vaccines for Ebola and Venezuelan/Eastern/Western equine encephalomyelitis viruses.
*In order to go through the in vivo testing, researchers need to know which animal models are susceptible to SARS-COV-2 and develop similar clinical signs to humans. There is a lot of work being done right now to determine which animal models will work best to evaluate this particular virus. The laboratory mouse is a powerful tool; researchers know so much about the mouse genome that with current technology, they can genetically engineer a mouse (even humanize its immune system) to help target specific research questions. The key is finding which specific animals are susceptible to infection. Sometimes the mouse or other animal may become susceptible after the virus is passaged (“adapted”) through their species several times. Once the various animal models are known as mentioned above, they can be used to study viral pathogenesis, and evaluate not only vaccines, but different antivirals and therapeutics.
JB: At least a year. The only way to shorten that timeline is to not do clinical trials, and the potential risk associated with that a significant. Clinical trials are the only way to make sure that a vaccine is safe.
MH: With the jumpstart from the 2004 SARS experience. MERS, and the advances in molecular technology and open source databases, it will be an unusually fast process as far as vaccine development is concerned. Also, having the FDA and other regulatory systems onboard with the fast-tracking of promising vaccine candidates helps. Data is currently being collected from the first round of vaccine trials from the current COVID-19 outbreak. Even if this vaccine is proven safe and effective, though, it’s at least a year before it will be available for general use.
Q7: Is there a chance that other forms of treatment, such as antivirals, might be effective?
MH: Antiviral drugs are a promising strategy for coronavirus treatment. Many potential antiviral treatments are already available for other purposes and approved for human use.
Antiviral drugs may not stop viral infection but they may help reduce both the duration and severity of the disease. In a global pandemic, every patient you can prevent from being hospitalized and every day you can reduce a patient’s hospital stay are invaluable to the healthcare system stability.
Nucleotide analogs, which bind to viral nucleic acid sequences and throw a wrench into the molecular gears of the virus, are one promising antiviral drug track. Two drugs, in particular, remdesivir (originally developed by Gilead Pharmaceuticals to fight Ebola virus), and ribavirin (developed to fight Hepatitis C) have shown promise in China.
Another class of antiviral drugs with great potential are protease inhibitors. These are drugs that block the proper processing of the machinery the virus kicks in after entering the cell to initiate the production of the non-structural proteins (nsps) responsible for viral replication. The HIV drug, Kaletra (ritonavir + lopinavir), was successfully used to reduce SARS symptoms in the 2003 China outbreak. Favipiravir, an RNA polymerase inhibitor used to treat influenza and the anti-malarial drug, chloroquine, are in human trials for the current COVID-19 pandemic.
Another strategy is to tweak the host cellular response by both increasing the good host responses, like the anti-viral activity of interferon and/or decreasing the acute inflammatory response, i.e. IL-6, that causes much of the cellular pathology. The rheumatoid arthritis drugs, Actermra (tocilizumab) and Kevzara (sarilumab) are also approved and ready for human testing.
LE: There certainly is. SARS, a similar cornavirus, was able to be treated with antivirals. The process for evaluating antivirals and therapeutics is similar to the process for finding and evaluating vaccines (see my response to Q6).
Q8: What has this outbreak taught us (so far) about modern pandemics?
JB: Our instant communication is both a blessing and a challenge. The ability to stay connected while quarantined is incredibly helpful because we are social creatures and we need that connection. But the circulation of misinformation about the virus presents a unique type of challenge. I think the thing that stands out the most about this pandemic is that we should pay closer attention attention to the experiences of the first few cities that experience the pandemic, and prepare earlier. An announcement in early January encouraging people to gradually build up a two-week supply of food and essentials might have prevented the run-on supplies that we saw in so many locations.
LE: Certainly this outbreak speaks to how interconnected/global our society has become. With rapid international travel, it’s easy for the disease to spread from one hot zone to a naive population. This outbreak has illustrated how easy it is to fall behind in preparations, and a lack of preparation leads to an overwhelmed healthcare system. It’s important to have an outbreak plan at a local and governmental level. Already we’ve seen hospitals and research facilities scrambling to source enough personal protective equipment (PPE) to keep their workers protected and help slow disease spread. Much PPE is single-use, and as supplies dwindle, this outbreak has also illustrated how important it is to invest in re-usable and accessible PPE going forward. On a positive note, international collaborations have certainly sprung up to share resources and information as the healthcare and research worlds work to minimize disease impact and create a cure.
MH: First and foremost, we now know for a fact a global pandemic as a reality and not just something which happens only in developing countries. For at least thirty years, the science community has warned of the potential for a global pandemic. For most of us, we’ve treated these outbreaks as something that happens elsewhere.
Not any more.
We now know these rapidly-spreading infectious events can happen anywhere and at any time. I hope this will shine a spotlight on the need for infrastructure upgrades in our surveillance and response capabilities across the globe. Finally, we’ve learned the value of sharing information through science databases and open-source, peer-reviewed databases held under rigorous standards.
Readers: What other questions do you have about SARS-COV-2 and COVID-19?
Ask them in the comments below, and our experts will try to respond.
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