by Dr. Daniel Wexler 4/1/2020
Our Battle With Nature
Humans are engaged in a brutal battle with nature. People have been effective at turning their environment on its head for short-term gain, often in ways that in the long run are self-defeating. As such, climate change is an existential threat, not necessarily for the continuity of the species but rather for the continuity of the status quo. Crop zones march toward the poles, tropical rain forests turn to grassland, storms become more frequent and devastating, oceans rise and acidify, some areas become too wet and some too dry...the litany of change goes on. Islanders move to the mainland, coastal dwellers move inland, real estate rises and falls, the economy rises and falls, and human behavior shows both its beauty and its ugliness.
Viruses know nothing of this. We can argue whether or not they are even alive, but one thing we cannot argue about is that they exist and they do what we try to do: survive in a changing world. But what are viruses and what is their relationship to human beings?
What is a Virus?
A virus is a remarkably tiny and infectious space ship of sorts that consists of a protein chamber called a capsid, inside of which is a dollop of genes in the form of RNA or DNA. There may also be external accessories such as a fatty layer called an envelope as well as projections that enable the bug to interact with its host. It can't reproduce on its own, it can't eat or drink, it can't produce its own energy. That is why it must enter a living cell to commandeer the fruits of those capabilities and direct the machinery of the cell to make perfect copies ready to continue the cycle of self-perpetuation. The cell then hatches (and dies) to release the new virus particles, or else the "babies" squeeze through the cell membrane without busting it open.
Where Did Viruses Come From?
Nobody knows how viruses first came into being. Perhaps they began as parasites that degenerated from their original cellular form, but other hypotheses abound. It was interesting, however, to find that some have welded themselves inside cell genomes and once thought to be junk are now believed to serve as a source of material for future evolution. Unnervingly, virus-related DNA (transposable elements and retroviral genomes) account for fully half of all the DNA in humans, much more than the 1% occupied by genes; most of these sequences are "fossilized" and inactive, but a few actually contain or control genes that do important things such as guide placental development in mammals and enhance the response to infection.
How Do Viruses Spread?
Viruses spread in a variety of ways: some by blood suckers such as mosquitoes, by breathing, eating and drinking, through contact with fecal material, and through sex. They often are species-specific, but some are shared between different kinds of animals, for example chickens and pigs, and pigs and people. This is how new diseases enter human populations, quickly evolving to be a better fit for transmission between people and therefore more contagious. A virus will generally not evolve to be too deadly - in that sense it will be easy to transmit but not too hard on its victims. After all, a dead host is lousy at giving its disease to others. That is why viruses which cause the common cold (mostly rhinoviruses, non-SARS coronaviruses, and a multitude of unknown types) are among the most successful of these agents - how many people do you know (including yourself) have gone to work with a case of the sniffles and passed on their cold?
Of course, simply landing on a mucus membrane in a potential host is not going to land the virus a job. There are obstacles such as watery mucus and beating cilia to drive the mucus up and out. One idea is that cold, dry weather is conducive to seasonal flu because the mucus coating themselves become dryer and thinner and the cilia struggle to move the virus out. Or it could be that the body's innate immune system becomes less robust. The innate immune system (built around a large set of bioactive molecules) is the primary bulwark against infection of this sort. It acts quickly and has the advantage that it doesn't care what the invader is, quite unlike the slow, long-lasting and highly specific adaptive immune system (mobilizing antibodies and killer T-cells) that only kicks in weeks after an infection is in place.
What is Coronavirus SARS-CoV-2?
Coronaviruses are a type of RNA virus that primarily causes upper-respiratory infections. This type of virus evolves fairly rapidly because every time it replicates in a cell it accumulates a handful of mutations due to poor fidelity in the RNA replication process. Most of these mutations do not affect the way the virus acts, but occasionally one does occur that is significant. As these changes accumulate the virus evolves, especially when there is an opportunity to enter new host pools. SARS-CoV-2, which causes the disease Covid-19, was found to be closely related genetically to a coronavirus found in bats. It is presumed that it jumped from bats directly, or via another animal, to people in Chinese wet markets. Unlike the 2003 SARS "classic", which required a series of mutations to adapt to humans, this form of the coronavirus was already highly contagious. The well-attuned nature of this iteration of the virus also predisposed it to cause severe symptoms in certain people.
How Does This Coronavirus Cause Infection?
Anatomically, coronaviruses are studded with spikes topped with crowns (hence "corona", Latin for crown). The crowns are like balls that fit into perfectly shaped gloves embedded in the surfaces of cells lining the respiratory tract. These gloves are actually proteins called ACE2, and these are common among cells of the airways, including the lungs. So, unlike normal cold viruses which make their home in the nasopharangeal passages, SARS-CoV-2 also penetrates into lung tissue where in some people it causes havoc so severe that the victim dies of respiratory failure (although other body systems such as the heart and GI tract can also be affected). Viruses that infect the lungs are not very contagious, but this one has a duality that makes it a stealth warrior - its early and symptom-free existence in the nasal passages appears to allow it to be spread to other people before the symptoms of deeper infection, like fever and dry cough, take hold. Equally insidious, it may subsist there after symptoms have abated since patients have been shown to shed virus for up to several weeks after recovery.
The Immune Response to the Virus
The body responds to viral invasion by mounting an immune response. Like an army, the body's anti-viral defenses are divided into separate divisions - the one that acts quickly and non-specifically is the innate immune system. This rapid response consists of the production of a variety of bioactive molecules by cells of the infected tissues. It is followed a few weeks later by the adaptive response, captained by specialized white blood cells that stimulate the manufacture of antibodies or activate search-and-destroy T-cells.
The Innate Immune System Goes Haywire in Some Covid-19 Patients
The hallmark of the first-line innate response is "acute inflammation". This involves a stewpot of pro-inflammatory cytokine proteins, most relevant the chemokines and interleukins, which are secreted by cells in response to virus invasion. In some Covid-19 patients, the lungs are subjected to cytokine dysregulation, otherwise termed a "cytokine storm", in which the cytokine response is too extreme for the situation. This results in a rapid fluid buildup in lung alveoli and consequent pneumonia and respiratory failure. The alveoli are the microscopic sacs in which gases (oxygen and carbon dioxide) are exchanged back and forth with the blood circulatory system. If the capillary blood vessels feeding the alveoli become too leaky at the direction of out-of-control cytokines, the sacs become flooded with fluid or pus; blood oxygen levels then decline causing shortness of breath, "air hunger", and cyanosis. Carbon dioxide also builds up causing rapid, shallow breathing and mental confusion. Once on a respirator, even if a critical patient is resuscitated and survives the lungs might be damaged not just from pneumonia but from the bursting of alveoli under high air pressure.
How Do We Predict Who Will Become Critically Ill?
As with influenza, the elderly and immunocompromised are far more susceptible to severe illness presumably because the immune system in some unknown way is less robust than in younger individuals. Influenza also puts very young children, who have undeveloped immune systems, at risk, but paradoxically Covid-19 has less of an impact on this population. This is not to say that less-at-risk people don't succumb to this disease - they do. Infectious disease researchers are intensely interested in exploring the factors underlying severe disease susceptibility, including gene variants, immune system status, microbiome composition, viral load, and underlying health/behavioral conditions such as cancer, diabetes, alcoholism, narcotics abuse and smoking. One small scale study has suggested that people most at risk have experienced a combination of deep muscle pain (considered a marker for inflammation), elevated hemoglobin (which is linked among other things to smoking), and mysteriously to a slight increase in the liver enzyme alanine aminotransferase (ALT), a marker for liver damage. It has also been suggested that high viral load and repeated exposures may play a role; this would certainly explain why emergency and ICU physicians and nurses die more frequently than expected once infected.
What Should We Expect as the Year Progresses?
Seasonal influenza peaks in winter and reaches a nadir in the summer months. It is unknown if Covid-19 will behave similarly. We do know that this novel virus is contagious in tropical regions (such as Singapore in Southeast Asia) and in the southern hemisphere (ex. Australia) where the seasons are reversed. We will have more information as the year progresses, but perhaps a more critical factor is the presence of large concentrations of people who have never been exposed to the virus and are therefore not immune. For example, physicians in India worry that residents of impoverished urban areas are at extreme risk of contagion due to overcrowding, poor sanitation, and unavailability of face masks. Physical distancing, and even handwashing, are unrealistic in many areas.
Even if the pandemic tamps down for summer, this effect will likely be temporary and the virus is expected to re-emerge in the fall (as was the pattern for the devastating 1918-1919 flu pandemic), especially if physical-distancing measures wane. Relaxing restrictions out of economic concerns, as China has done, is a dangerous game, especially when opening the economy entails international travel. This is complicated by the fact that different countries are in different stages of the pandemic, meaning that this could go on for a long while. In the end, it comes down to a moral tradeoff between saving lives and saving economies.
Each nation will have to look within its collective soul to find its highest priorities. Destruction can be transformative if it creates a moral spirit that transcends self-interest to bring people together as a single community with a common purpose. If we value human life and spirit then this could be a golden opportunity to restructure society in a form that is both cohesive and humane. Covid-19 is only one manifestation of a plethora of disease onslaughts, both viral, bacterial, and fungal, which are bound to test our will and the strength of our societies. As if that were not enough, climate change has been in code red for years and is now literally lapping at our feet. This begs the question: will we learn our lesson from the Great Pandemic of 2020 - that even a short delay in mitigation has profound implications for human life? Can we extend that lesson to planet Earth and muster the political will to quickly reverse the damage we have inflicted on the very ecosystems we depend on for survival?